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Journal of Signal Transduction
Volume 2011 (2011), Article ID 195239, 8 pages
Protein Tyrosine Phosphatase SHP-2 (PTPN11) in Hematopoiesis and Leukemogenesis
Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
Received 16 February 2011; Accepted 1 April 2011
Academic Editor: David Leitenberg
Copyright © 2011 Xia Liu and Cheng-Kui Qu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
SHP-2 (PTPN11), a ubiquitously expressed protein tyrosine phosphatase, is critical for hematopoietic cell development and function owing to its essential role in growth factor/cytokine signaling. More importantly, germline and somatic mutations in this phosphatase are associated with Noonan syndrome, Leopard syndrome, and childhood hematologic malignancies. The molecular mechanisms by which SHP-2 mutations induce these diseases are not fully understood, as the biochemical bases of SHP-2 functions still remain elusive. Further understanding SHP-2 signaling activities and identification of its interacting proteins/substrates will shed light on the pathogenesis of PTPN11-associated hematologic malignancies, which, in turn, may lead to novel therapeutics for these diseases.
1. Introduction
SHP-2, encoded by PTPN11, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that contains two tandem Src homology 2 (SH2) domains, a PTP domain, and a C-terminal tail with tyrosyl phosphorylation sites and a prolyl-rich motif [1–5]. It shares a similar overall structure and high homology with SHP-1, another SH2 domain-containing PTP that is predominantly expressed in hematopoietic cells [6, 7]. However, SHP-2 and SHP-1 play opposing roles in hematopoietic cell function [8–10]. Genetic analyses using the Xenopus model have revealed that both the SH2 domains and the PTP domains contribute to their signaling and thus functional specificities [11, 12]. The 2.0 Å X-ray crystal structure of SHP-2 reveals that the protein is self-inhibited by the binding of the N-terminal SH2 (N-SH2) domain to the PTP domain via hydrogen bonds [13, 14]. Upon growth factor/cytokine stimulation, binding of SHP-2 via its SH2 domains to phosphorylated tyrosine residues on growth factor receptors or docking proteins results in disruption of the autoinhibitory interaction, leading to exposure of the catalytic site and enzymatic activation [13, 14]. Remarkably, mutations in PTPN11 have been identified in several human diseases, such as the developmental disorders Noonan syndrome (NS) [15] and Leopard syndrome (LS) [16, 17], childhood hematologic malignancies [18–20], and sporadic solid tumors [21]. Most of these disease-associated mutations affect N-SH2 or PTP domain residues involved in the basal inhibition, resulting in either "activated mutants" or "inactivated mutants" of SHP-2. Although significant progress has been made in the past years, signaling mechanisms of SHP-2 and the molecular mechanisms by which SHP-2 mutations are associated with human diseases are still not fully understood. Emerging evidence has indicated that SHP-2 may also have important functions in the nucleus and the mitochondria [22–24]. Better understanding the role of SHP-2 in these organelles may provide new insights into the pathogenesis of SHP-2 mutation-associated human diseases. This paper focuses on the physiological and pathological roles of SHP-2 in hematopoietic cell development and leukemogenesis.
2. SHP-2 in Cytoplasmic Signal Transduction
SHP-2 is primarily localized to the cytosol and has been implicated in cell signaling initiated by growth factors, cytokines, and hormones, regulating cell survival/growth and differentiation [8, 25]. In addition, SHP-2 modulates cell adhesion molecules-induced signal transduction and has been found to play an important role in cell migration and motility [26–30]. This phosphatase plays complicated roles in cell signaling processes. It is involved in a variety of cell signaling cascades, such as the RAS-MAP kinase, JAK-STAT, PI3K-AKT, Rho, NF-κB, and NFAT pathways [8, 25]. Furthermore, it acts at multiple sites in individual pathways. SHP-2 appears to function in cell signaling in both catalytic-dependent and -independent manners. While its catalytic activity is important for cell signaling, SHP-2 can also function as an adaptor independent of catalytic activity [31–33]. Despite extensive studies over the past decade, the mechanisms of SHP-2 action are still poorly defined. SHP-2 interacts with a number of cell signaling components, such as growth factor/cytokine receptors, SIRPα/SHPS-1, PZR, Grb2, FRS, IRS-1, Gab1, Gab2, p85, STAT5/3/1, and Sprouty [8, 25]. Of these partners, some are the targets of SHP-2 enzymatic activity. However, none of the putative substrates identified to date can fully account for the signaling effects of SHP-2 on the many biological processes with which it has been implicated. PTPs were originally thought to be negative regulators owing to their opposite roles to protein-tyrosine kinases (PTKs). However, SHP-2 is a PTP that plays an overall positive role in many cell-signaling processes, in particular, the RAS-ERK pathway, promoting cell growth and differentiation. The underlying mechanisms remain elusive. In most cases, SHP-2 is considered to regulate an upstream element necessary for RAS activation; yet, SHP-2 functions downstream of, or parallel to, RAS activation have also been demonstrated [34]. The PTP activity of SHP-2 has been shown to be required for full activation of RAS. Three possibilities have been proposed [35]. First, SHP-2 promotes RAS activation by dephosphorylating tyrosine-phosphorylated sites of receptor PTKs or docking proteins that bind p120 RAS-GTPase activating protein (RAS-GAP), a negative regulator of RAS activity; second, SHP-2 potentiates activation of Src family kinases (SFKs) by dephosphorylating Csk (a negative regulator of SFKs) binding protein (Cbp), thereby preventing access of Csk to SFKs. Enhanced activation of SFKs in turn leads to optimal RAS activation; finally, SHP-2 promotes RAS activation by dephosphorylating Sprouty, another negative regulator of RAS. Although in most circumstances, SHP-2 plays a positive role in transducing signals relayed from receptor PTKs, SHP-2 can also function as a negative regulator depending upon stimuli, binding partners, and interacting downstream signaling networks [36]. For example, it negatively regulates JAK/STAT signaling initiated by interferon-α and -γ [37]. Another prominent example is that SHP-2 negatively regulates gp130 signaling triggered by leukemia inhibitory factor, ciliary neurotrophic factor, and interleukin-6 (IL-6) [38, 39].
3. SHP-2 in the Nucleus and the Mitochondria
Emerging evidence shows that SHP-2 is distributed to the nucleus and the mitochondria, where it can also have important functions [22–24]. Prolactin stimulation of mammary cells leads to the nuclear translocation of SHP-2 as a complex with STAT5 which then binds to DNA and regulates transcription of milk protein genes [22]. Also, it has been demonstrated that nuclear SHP-2 dephosphorylates STAT1 and STAT3 at tyrosine and serine residues and thus inhibits their transcriptional activities [40, 41]. Recently, SHP-2 has been found to inhibit nuclear export of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, in the nucleus by dephosphorylating Tyrosine707 of TERT, thereby enhancing nuclear telomerase activity [42]. Since telomerase plays an important role in maintaining telomere length and shortening of telomeres has been linked to chromosomal instability and cell aging, SHP-2 may thus be involved in the regulation of aging processes. Our previous studies showed that about 30%–40% of SHP-2 is localized to the nucleus in mouse embryonic fibroblasts and that SHP-2 plays an important role in DNA damage-induced cellular responses [23]. SHP-2 promotes DNA damage-induced apoptosis by enhancing the c-Abl kinase-mediated pathway [23]. It is also required for DNA damage-induced translocation of Cdc25C from the nucleus to the cytoplasm [43]. Loss of functional SHP-2 decreases DNA damage-induced apoptosis as well as the cell-cycle checkpoint (G2/M) response [23, 43]. Using "rescue" approaches, we have defined that SHP-2 functions in DNA damage-induced c-Abl activation, and thereby apoptosis, in a catalytic-dependent manner, whereas its role in the DNA damage-induced G2/M checkpoint does not require catalytic activity [44].
SHP-2 is also distributed to the mitochondria, specifically the intercristae/intermembrane space (IMS) [24, 45]. However, the role of SHP-2 in the mitochondria remains unclear. The mitochondrial oxidative phosphorylation (OxPhos) system provides the vast majority of cellular energy and produces reactive oxygen species (ROS). Recently, Lee et al. propose that OxPhos complexes might be direct or indirect targets of SHP-2 [46]. They have found that cytochrome c oxidase (CcO) activity and ROS levels are significantly increased, whereas mitochondrial membrane potential and ATP content are decreased in constitutively active SHP-2 mutant cells. CcO subunit II can be phosphorylated by Src kinase which is also localized to the IMS [47, 48]. As it has long been recognized that cytosolic SHP-2 and Src regulate each other, their observations raise the possibility that SHP-2 enhances CcO activity in the mitochondria by activating Src kinase. However, other signaling pathways may also be affected by mitochondrial SHP-2. Identification of mitochondrial substrate(s) and downstream target(s) of SHP-2 will shed light on the molecular mechanisms by which SHP-2 regulates mitochondrial function and mitochondria-dependent cellular activities.
4. SHP-2 in Normal Hematopoiesis and the Immune System
Hematopoiesis is the cellular process in which all types of blood cells including erythroid, myeloid, and lymphoid cells are produced from pluripotent hematopoietic stem cells (HSCs). It is tightly controlled by environmental cues, such as cytokines and growth factors. Dysregulation of cytokine/growth factor signaling can result in blood disorders, including hematologic malignancies. SHP-2 is highly expressed in hematopoietic cells. Our previous studies have demonstrated that in contrast to the highly related SHP-1 phosphatase which negatively regulates hematopoietic cell development [49, 50], SHP-2 plays an overall positive role in hematopoiesis [51–53]. N-SH2 deletion generates a loss of function mutation in SHP-2. This mutation severely suppresses the development of erythroid and myeloid progenitors in homozygous mutant embryos [51]. Consistent with this result, neither erythroid nor myeloid progenitors derived from mutant embryonic stem (ES) cells with the N-SH2 deletion mutation in SHP-2 were detectable in the fetal liver or bone marrow of the chimeric animals generated from these ES cells [52]. In addition, SHP-2 is required for lymphopoiesis [53]. In Rag2-deficient blastocyst rescue experiments, differentiation of lymphoid lineages from ES cells with the N-SH2 deletion mutation of SHP-2 was blocked before pro-T- and pro-B-cell stages [53]. These data suggest that SHP-2 is required for the development of all blood cell lineages. Recent studies have demonstrated that SHP-2 plays a critical role in the survival and maintenance of HSCs. Even heterozygous N-SH2 deletion mutation in SHP-2 causes the HSC pool to reside in a less quiescent (G0) state. HSC repopulating capacity and self-renewal are markedly reduced by this mutation [54]. Furthermore, depletion of SHP-2 from hematopoietic cells in SHP-2 conditional knockout mice results in rapid loss of HSCs and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner [55].
The signaling mechanisms by which SHP-2 regulates hematopoietic cell development and function are not well understood. SHP-2 participates in the signal transduction of many hematopoietic cytokines, such as IL-3, IL-5, IL-6, IL-9, IL-11, EPO, SCF, GM-CSF, M-CSF, and Flt3-ligand [9]. SHP-2 appears to promote hematopoietic cell development by positively regulating critical signaling processes of hematopoietic growth factors/cytokines. We have demonstrated that SHP-2 is required for the signal transduction of IL-3, a cytokine involved in hematopoietic cell survival, proliferation, and differentiation [33]. IL-3-induced activation of JAK/STAT, ERK, and PI3K pathways in hematopoietic cells with N-SH2 deletion mutation of SHP-2 was impaired [33]. However, in catalytically deficient SHP-2 C459S-overexpressing cells, IL-3-induced PI3K activation remained unaltered, while activation of JAK2 and ERK was reduced [33]. These observations suggest that SHP-2 plays multiple roles in IL-3 signal transduction, acting in both catalytic-dependent and -independent manners in the JAK/STAT, ERK, and PI3K pathways (Figure 1). Interestingly, SHP-2 also has a negative effect on hematopoietic cell survival. Overexpression of wild-type SHP-2 in hematopoietic cells compromised their hematopoietic activities and enhanced cytokine deprivation-induced apoptosis by dephosphorylating STAT5 [56].
SHP-2 also plays an important role in the regulation of the immune system through its effects on cytokine and inhibitory receptor signaling pathways [57]. In addition to its well-established role in cytokine responses, SHP-2 has been implicated as an important mediator of inhibitory receptor signaling. Inhibitory receptors contain one or more immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their cytoplasmic domains essential for generation and transduction of inhibitory signals. Tyrosine phosphorylation of the ITIM allows it to bind and activate phosphatases containing SH2 domains. SHP-2 has been found to be recruited to several inhibitory receptors, including the T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1), B- and T-lymphocyte attenuator (BTLA), killer cell Ig-like receptors (KIRs), CD31 in lymphocytes, and ITIM-containing receptors in granulocytes and platelets [57]. The role of SHP-2 in T cells is still controversial. Frearson and Alexander [58] showed that SHP-2 played a positive role in T cell receptor (TCR) signaling. Expression of catalytically deficient SHP-2 C459S significantly inhibited TCR-induced activation of ERK, but had no effect on TCR-zeta chain tyrosine phosphorylation or TCR-elicited Ca2+ transients. However, another study implicates SHP-2 as a negative regulator in TCR signaling [59]. Overexpression of Gab2, a critical downstream substrate/target of SHP-2, in T cells resulted in downregulation of TCR-mediated NFAT activation and IL-2 production [59]. Gab2 mutants lacking SHP-2-binding sites abrogated the inhibitory activity of Gab2, but its inhibitory function was restored by fusing to active SHP-2 as a chimeric protein, suggesting that the inhibitory function of Gab2 is largely dependent on SHP-2 [59]. Additionally, SHP-2 might be involved in the downregulation of T-cell adhesion processes [60]. TCR-induced ROS production selectively inhibits SHP-2-mediated dephosphorylation of Vav1 and ADAP associated with SLP-76, which limits TCR-induced adhesion and integrin clustering [60]. In consistent, overexpression of SHP-2 C459S enhanced TCR-induced LFA-1 clustering and the adhesion of Jurkat T cells to fibronectin [60].
Recent mouse studies have provided new insights into the role of SHP-2 in immune responses. Transgenic mice with expression of dominant-negative SHP-2 C459S in T cells have normal T cell development but display increased T cell activation in vivo, and aged mice have elevated serum antibodies [61]. In addition, phosphorylation of the adaptor LAT (linker for activation of T cells) downstream of TCR stimulation is defective in SHP-2 C459S T cells, whereas SHP-2 C459S-expression does not affect the majority of TCR-induced tyrosine phosphorylation, ERK activation, and TCR-driven proliferation [61]. These results suggest that wild-type SHP-2 plays an important role in suppressing the differentiation of T cells to a Th2 phenotype. Considering that overall TCR response is unchanged in SHP-2 C459S-expressing mice, it is likely that the phenotypes observed in the SHP-2 C459S transgenic mice may not be due to direct effects of SHP-2 on TCR-mediated signaling but rather on signaling pathways downstream of other receptors. However, this conclusion was challenged by more recent studies with selective SHP-2 depletion in thymocytes [62]. Lck-Cre-mediated deletion of SHP-2 in the thymus resulted in a significant block in thymocyte differentiation/proliferation and reduced expansion of CD4+ T cells. Furthermore, SHP-2-depleted mature T cells showed decreased TCR signaling in vitro. These data supports that SHP-2 is a common signal transducer for pre-TCR and TCR in promoting T cell maturation and proliferation.
5. PTPN11 Mutations in Hematologic Malignancies
Notably, germline mutations in PTPN11 (SHP-2) are found in ~50% of the cases with the developmental disorder NS [15] and nearly all patients of the developmental disorder LS that shares certain features with NS [16, 17]. Moreover, somatic mutations in PTPN11 occur in about 35% of the patients with juvenile myelomonocytic leukemia (JMML) [18, 19], a childhood myeloproliferative disorder (MPD). In addition, PTPN11 mutations have been identified in pediatric acute leukemias, such as myelodysplastic syndrome (MDS) (10%) [18, 19], B cell acute lymphoblastic leukemia (B-ALL) (7%) [20, 63], and acute myeloid leukemia (AML) (4%) [64]. In contrast, PTPN11 mutations occur rarely in adult patients with MDS, AML, or chronic myelomonocytic leukemia (CMML) [65–67]. The reason for this is unclear. PTPN11 mutations found in NS and LS are clustered in the PTP domain, whereas most of the leukemia-associated PTPN11 mutations are located in the N-SH2 domain. NS and leukemia mutations cause changes in amino acids located at the interface formed by the N-SH2 and PTP domains in the self-inhibited SHP-2 conformation, disrupting the inhibitory intramolecular interaction, leading to hyperactivation of the catalytic activity [18]. Biochemical analyses have shown that SHP-2 mutants found in leukemias are more enzymatically active than those in NS [18, 68], suggesting that low levels of SHP-2 activation result in NS, whereas higher levels of SHP-2 activity may be required for leukemogenesis. PTPN11 mutations found in LS are located in the PTP domain, also causing changes in amino acids located at the interface formed by the N-SH2 and PTP domains and disrupting the intramolecular interaction. However, these mutations result in inactivation of the enzymatic activity due to the changes in key catalytic amino acid residues in the phosphatase active site [69].
Recent studies have begun to elucidate the pathogenesis of PTPN11 mutation-associated diseases. Heterozygous PTPN11 D61G and PTPN11 Y279C knock-in mice develop NS, and LS phenotypes, respectively, strongly suggesting a causal role of PTPN11 D61G and PTPN11 Y279C mutations in the pathogenesis of these two diseases [70, 71]. Moreover, PTPN11D61G/+ mice develop moderate MPD, characterized by excessive myeloid cell expansion and hepatosplenomegaly [70]. Myeloid progenitors from these mutant mice are hypersensitive to cytokines (GM-CSF and IL-3), reminiscent of JMML, the hallmark of which is the hypersensitive pattern of myeloid progenitor colony growth in response to GM-CSF [72]. Our recent studies showed that GM-CSF and IL-3-induced ERK and AKT activation was enhanced in PTPN11D61G/+ macrophages and mast cells [73]. Clearly, aberrantly enhanced cytokine signaling contributes to the excess expansion of myeloid cells in these mutant animals. More importantly, PTPN11D61G/+ mutation also aberrantly activates HSCs. This mutation accelerates HSC cycling, thereby increasing the stem cell pool and elevating short-term and long-term repopulating capabilities [73]. Inducible knock-in mice expressing the leukemogenic allele PTPN11D61Y in hematopoietic cells develop fatal MPD [74]. PTPN11D61Y/+ mutation decreases the HSC pool and the percentage of HSCs in G0 phase in the bone marrow, whereas the number of HSCs was markedly increased and larger proportion of HSCs are quiescent in the spleen [74]. These data suggests PTPN11D61Y/+ mutation drives HSCs in the bone marrow out of the quiescence, and they migrate from bone marrow to the spleen. Although global PTPN11D61G/+ mice similarly show the increased HSCs in the spleen, and quiescent HSCs are also decreased in the bone marrow, the overall HSC pool in PTPN11D61G/+ bone marrow is increased [73]. Since the D61Y mutation is more potent than the D61G mutation in enhancing the catalytic activity of SHP-2, the difference in HSC phenotypes caused by these two mutations suggests that the pathogenic effects of PTPN11 mutations on HSC homeostasis is dependent on the level of SHP-2 catalytic activity. In addition, stem cell microenvironments of these two mouse models may also contribute to the different HSC phenotypes. Unlike PTPN11D61Y/+ inducible knock-in mice where the mutation is primarily within the hematopoietic compartment, PTPN11D61G/+global knock-in mice carry the same mutation in all tissues and cells, including endothelial, osteoblasts, and other stromal cells that compromise the microenvironment for HSCs. PTPN11D61G/+ mutation in the microenvironment may exert certain detrimental effects on HSC homeostasis by altering cytokine/growth factor secretion. Thus, the HSC phenotypes caused by PTPN11D61G/+ germline mutation may represent a combined effect of PTPN11 mutation in HSCs and in the microenvironment.
The molecular mechanisms by which PTPN11 mutations induce hematopoietic malignancies are not fully understood. Hyperactive RAS signaling is the central event in the abnormal growth of malignant myeloid cells. Somatic RAS point mutations are found in ~20% of JMML [75] and ~40% of CMML cases [76], and NRAS or KRAS mutations occur in ~20% of AML specimens [77]. Given the positive role of SHP-2 in the RAS pathway, it is possible that PTPN11 mutations contribute to hematopoietic malignancies also by deregulating RAS-ERK signaling. However, other signaling pathways may also contribute to PTPN11-associated leukemogenesis. Studies from our laboratory and others have shown that leukemia-associated PTPN11 mutations also enhance multiple other hematopoietic signaling cascades, such as PI3K/AKT and JAK/STAT pathways [73, 74, 78, 79]. Mutant SHP-2 also has increased interactions with Gab2, Grb2, and p85, contributing to enhanced activation of these pathways [78]. Intriguingly, catalytically inactive SHP-2 E76K with an additional C459S mutation retained the capability to increase interaction with Gab2 and to enhance activation of the PI3K pathway, suggesting that in addition to the elevated catalytic activity, fundamental changes in physical and functional interactions between gain-of-function (GOF) mutant SHP-2 and signaling partners also play an important role in cytokine hypersensitivity. This notion is further supported by the fact that both NS and LS are associated with increased risk of hematologic malignancies although PTPN11 mutations found in NS and LS activate and inactivate SHP-2 enzymatic activity, respectively. It, thus, appears that catalytic activity of mutant SHP-2 is not fully responsible for the pathogenic effects. Rather, increased adaptor function of mutant SHP-2 also contributes to the enhanced downstream signaling. Consistent with this idea, LS mutations, like NS mutations, also enhance SHP-2 binding to signaling partners due to its protein conformational changes resulting from the mutations [69]. It would be interesting to see how LS mutation PTPN11 Y279C affects hematopoietic cell development in the mutation knock-in mice [71].
Other recent studies provide additional new insights into the mechanisms by which PTPN11 mutations induce hematologic malignancies. Konieczna et al. have found that the effect of leukemia-associated SHP-2 mutants on myeloid cell transformation involves inactivation of interferon consensus sequence-binding protein (ICSBP), which is an interferon-regulatory transcription factor that functions as a leukemia tumor suppressor [80]. ICSBP tyrosine phosphorylation during myelopoiesis is required for transcription of NF1, which subsequently inactivates cytokine-activated RAS, thereby creating a negative feedback mechanism for cytokine-induced proliferation [81]. Consequently, dephosphorylation of ICSBP by constitutively active mutants of SHP-2 inhibits ICSBP-dependent NF1 transcription, thereby impairing this negative feedback mechanism on cytokine-activated RAS and contributing to the proliferative phenotype in myeloid malignancies. In addition, the same group reported that HoxA10, a homeodomain transcription factor that represses myeloid differentiation genes, is also a substrate for SHP-2. As tyrosine phosphorylation of HoxA10 decreases its DNA-binding activity, enhanced dephosphorylation of HoxA10 by constitutively active SHP-2 synergizes with HoxA10 overexpression to accelerate disease progression to AML [82].
6. Perspectives
Since its discovery, tremendous progress has been made in understanding the physiological functions of SHP-2 and its clinical relevance to human diseases. However, there are still numerous questions that remain to be addressed. All of the available data support that GOF mutations in PTPN11 play a causal role in NS, LS, and JMML; however, whether the contribution of PTPN11 mutations to acute leukemias represents a primary event or a second hit acquired during disease progression is not conclusive. Moreover, upregulating the RAS pathway may be necessary but not sufficient for PTPN11 mutations to cause leukemias. Further studies are needed to find new signaling pathways and molecules disturbed by leukemia-associated mutant SHP-2. Finally, our current understanding is very limited regarding the role of SHP-2 in maintaining HSC functions. Fully characterizing how PTPN11 mutations deregulate HSC activity may provide new insights into the pathogenesis of PTPN11 mutation-associated acute leukemias and improve stem cell-based therapies.
This work was supported by the National Institutes of Health Grants nos. HL068212 and HL095657 (to C.-K. Qu) and Case Comprehensive Cancer Center Cancer Stem Cell Pilot Grant (to C.-K. Qu).
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- C. K. Qu, W. M. Yu, B. Azzarelli, S. Cooper, H. E. Broxmeyer, and G. S. Feng, "Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells," Molecular and Cellular Biology, vol. 18, no. 10, pp. 6075–6082, 1998. View at Scopus
- C. K. Qu, S. Nguyen, J. Chen, and G. S. Feng, "Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development," Blood, vol. 97, no. 4, pp. 911–914, 2001. View at Publisher · View at Google Scholar · View at Scopus
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- J. Chen, W. M. Yu, K. D. Bunting, and C. K. Qu, "A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival," Oncogene, vol. 23, no. 20, pp. 3659–3669, 2004. View at Publisher · View at Google Scholar · View at Scopus
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Complete statistics and more, for any player. Enter as much of the player's name as you know. |
Find statistics for every player in a single organization and navigate the farm system for any organization. Start by selecting an organization. |
View the statistic leaders for every league, individual and team and check to see the scoreboard for each league. |
Maikel Franco, 3b, Phillies
Proper Name: Maikel Antonio Franco Born: Aug. 26, 1992 in Azua, Dominican Republic High School: Ht.: 6-1 Wt.: 180 Bats: R Throws: R |

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Oklahoma Sooners
Print without images
Sunday, January 13, 2013
OU shores up defensive line with Walker
By Brandon Chatmon
Oklahoma continues to add bodies at the defensive tackle position.
Defensive tackle
Charles Walker
(Garland, Texas/South Garland)
picked the Sooners over North Texas, Houston, New Mexico and others on Saturday
. He should provide added depth to the position as OU looks to improve its defensive interior in 2013.
The Sooners began December with zero commitments at defensive tackle and have secured three commitments in the past six weeks, including junior college standout
Quincy Russell
(Athens, Texas/Trinity Valley).
While none of the names are eye-popping, Russell appears to be the best prepared to play in 2013. Walker and
Kerrick Huggins
(Dallas/Skyline), however, each have traits that could make them recruiting gems in the future. OU has secured much needed depth while finding players with long-term upside along the interior.
Walker has plenty of talent but injury concerns -- he just had labrum surgery -- could have scared some programs off. Regardless, the key for Walker and Huggins will be development once they arrive in Norman. Both players have unique physical traits, but those skills mean nothing if they cannot translate them into assets that allow them to create mismatches up front.
Walker, at 6-foot-4 and 280 pounds, brings unique athleticism for a player his size, but he is relatively raw. Don't expect an immediate impact from the recent commitment but his physical traits could allow him to emerge as a difference maker during his time in crimson and cream.
The senior defensive tackle is a example of OU's philosophy of waiting until after a player's senior season to further evaluate and offer. But, that philosophy will only pay off if OU develops Walker and Huggins into difference makers in the interior.
Make no mistake the Sooners are taking a chance with their wait-and-see approach along the defensive line and other positions. It could pay major dividends. Or it could lead to regrets and disappointment. On and off the field.


text: if you don't need a study what are you basing your claim on to begin with?... your calling prolegalization nonsense, when in reality you are being very ignorant and biased on the claims your making. it would be a good thing even for the government...when i drive and smoke i drive really fukin slow...so if i get in an accident its not going to be all horrible like they make it sound...bunch of dumbassess!..


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It's been a season of firsts since the opening of the Carnival Center for the Performing Arts. On the heels of the Miami debut of the Merce... More >>
He's been at this for a while, but even after more than 50 years before the public, there remains something weird and wonderful about Merce... More >>
Florida Grand Opera's new production of Bellini's La Sonnambula is not to be missed. One of the most demanding and beautiful of all operas... More >>
Puccini was not alone in loving this woman. The public first fell for her as the heroine of the sexy novel The Tale of the Chevalier Des... More >>


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Dictionary » N » Negative regulation Negative regulationnegative regulation negative feedback in biological systems mediated by allosteric regulatory enzymes. Please contribute to this project, if you have more information about this term feel free to edit this page Results from our forumGraphs depicting qPCR fold change... a scale from 0 to whatever, where values between 0 and 1 represent down-regulation, and values >1 represent up-regulation. But the problem with ... appreciate the extent of down-regulation. 2. Using inverse values where negative values (<-1) represent down-regulation and positive values (>+1) ...
See entire post
Problem with the normalization of PCR Ct values... gene mRNA" ? Finally if I want to present the data as 2^ΔCt, negative values mean down-regulation and positive values up-regulation? If you could suggest any literature dealing with ...
See entire post
Re: Theories - Origin of Life... touched. But, just to nail down this point, study this paper about the regulation by and of p53 master sensor of stress. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857175/ Tied Up in Loops: Positive and Negative Autoregulation of p53 In part it states Of these, p53/mdm2 is the master autoregulation ...
See entire post
Re: Theories - Origin of Life... often exhibit functional roles, such as gene expression, gene regulation, generation of genetic (antibody, antigenic, and other) diversity. ... Is this a positive argument for Darwinian macro evolution or simply a negative one against design.? Could you clarify please.
See entire post
Re: Theories - Origin of Life... systems in response to a major evolutionary challenge. The cellular regulation of natural genetic engineering automatically imposes a punctuated ... non-functional. In this sense, natural selection plays an essentially negative role, as postulated by many early thinkers about evolution (e.g. ...
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Seattle PD's statement on pot in Seattle due to the recently passed initiative decriminalizing less than one ounce of marijuana.
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Seattle PD's statement on pot in Seattle due to the recently passed initiative decriminalizing less than one ounce of marijuana.
Read more »f you were to put televangelist Pat Robertson, progressive media mogul Arianna Huffington, libertarian billionaire David Koch, and rap/reggae artist Snoop Dogg in a room together, do you think you could get them all to unanimously agree on anything?
Sounds like an impossible task. But actually there is common ground: they all believe our war on marijuana has failed. All of the above public figures believe in either the decriminalization or legalization of marijuana.
Read more »Ohio decriminalized possession of small cannabis amounts many years ago, but possession of paraphernalia remained a crime until this September.
Read more »Carrying less than half an ounce of pot is no longer a crime in Connecticut, but there are people who are still being prosecuted for doing exactly that.
The reason is they were busted before Connecticut's new decriminalization law took effect this month and some state prosecutors are pushing for convictions in some of those cases.
Read more »A bill downgrading the possession of an ounce or less of marijuana from a misdemeanor to an infraction has been signed into law by California Governor Arnold Schwarzenegger.
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Arizona Wildcats
Arizona Wildcats' win over Boston College: By the numbers
The Arizona Wildcats beat the Boston College Eagles 42-19 to win the AdvoCare V100 Bowl in Shreveport, LA. Here is a look at the game, by the numbers.
Arizona freshman receiver Trey Griffey caught three passes for 41 yards and two touchdowns, which were the first two scores of his Arizona career.
Boston College's Andre Williams, who was fourth in the Heisman voting and won the Doak Walker Award, was held to just 75 yards and one touchdown 26 carries, which averages out to 2.9 yards per tote.
Conversely, Arizona's Ka'Deem Carey, who finished 10th in the Heisman voting and was beaten out for the Doak Walker award, ran 28 times for 165 yards and two touchdowns, averaging 5.9 yards per run.
The Wildcats converted on 7-of-12 third down attempts.
Arizona freshman Nate Phillips caught a team-leading and career-high 9 passes for a bowl-record 194 yards.
The Eagles possessed the ball for 35:10, which was more than 10 minutes more than the Wildcats had it.
Boston College's Alex Amidon led all receivers with 10 catches, which he turned into 129 yards.
With Tuesday's win, Rich Rodriguez now has a 16-10 record to go along with a pair of bowl victories at Arizona.
Both Arizona QB B.J. Denker and Boston College QB Chase Rettig completed 17 passes on the afternoon, but the Wildcats' signal caller did so in three fewer attempts while throwing for 72 more yards. Rettig was also picked off twice, whereas Denker did not turn the ball over.
If this was Ka'Deem Carey's final game as an Arizona Wildcat, as many think it will be, then No. 25 went out in style. He will have finished his career with a good number of school records, a pair of All-American nods and two Pac-12 Offensive Player of the Year awards.
The Wildcats held a 29-point lead at the half, as they were up 35-6. It was their second-largest halftime advantage this season, trailing only the 45-6 edge they held against UNLV in the second week of the season.
It took the Wildcats all of 41 seconds to drive 92 yards for their first touchdown of the game in the first quarter.
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- Dave Pasch- ESPN play-by-play announcerDave Pasch believes that Steve Keim doesn't want Adrian Peterson to get away again.
- Bearing Down with Adam and Jarrett - Feb. 25, 2014Adam and Jarrett talk about a close call vs. UCLA and what it means for the Wildcats.
- Michael DeCourcy, college basketball analystDeCourcy says Arizona could be Kentucky's biggest hurdle in the NCAA Men's Basketball Tournament.
- Greg Byrne, UA Athletic Director The Wildcats Athletic Director talks about changing the perception of UA sports.
- Ray Anderson- ASU athletic directorRay Anderson has only seen his men's basketball team win when they play Arizona at Wells Fargo Aren


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USU Women's Basketball Picked Sixth In Mountain West Preseason Poll
Oct. 15, 2013 LOGAN, Utah - Utah State women's basketball was selected sixth in the Mountain West Women's Basketball Preseason Poll as voted on by a panel of the league's 11 head coaches and media. The poll was announced Tuesday morning by the conference, prior to the league's media days at the conference office in Colorado Springs, Colo. Fresno State, coached by former USU head coach Raegan Pebley, was picked to finish first in the conference with 238 points, including 17 first-place votes. The Bulldogs captured the 2013 Mountain West Tournament. Wyoming was tabbed second with 212 points, including four first-place votes, while the 2013 MW regular-season champion San Diego State was chosen third with 196 points and two first-place votes. New Mexico (185 points) and UNLV (170 points) were voted fourth and fifth, respectively with the Rebels taking the final two first-place votes. Utah State was picked sixth with 136 points, just ahead of Colorado State at seventh with 130 points. Boise State (96 points), San José State (76), Nevada (62) and Air Force round out the poll finishing eighth-11th respectively. Wyoming junior Kayla Woodward was named the 2013-14 MW Preseason Player of the Year. Woodward, a forward, was a second-team all-Mountain West selection last season and was named to the 2013 MW all-Tournament Team. Woodward, the top returning scorer in the league, averaged 14.1 points per game in 2012-13. She is joined on the preseason team by Colorado State's Sam Martin, Fresno State's Taylor Thompson, San Diego State's Erimma Amarikwa, and San José State's Ta`Rea Cunnigan. San Diego State's Chloe Johnson was named Preseason Freshman of the Year, while San Diego State transfer Cierra Warren earned Preseason Newcomer of the Year honors. Utah State enters its first season in the Mountain West Conference, bringing back six letterwinners from last year's squad that finished the season 18-14, finishing second in the Western Athletic Conference with a 14-4 league record. USU also advanced to the postseason for the third-straight season playing in the Women's Basketball Invitational (WBI). The Aggies will have to replace all-WAC honorees Devyn Christensen and Jenna Johnson from the starting five, but do return senior guard Jennifer Schlott, junior center Franny Vaaulu and sophomore guard Makenlee Williams from the starting lineup.
The Aggies have seven new players on the roster this season, including transfers guards Mariah Miles (Oral Roberts) and Jasmine Porter (San Diego State), who both sat out last season. USU welcomes three freshmen guards in Elizabeth Landreth, Shelby Cloninger and Lynette Johnson. International transfers forward Tijana Djukic and guard Ingrida Strikas both will be immediately available this season. USU head coach Jerry Finkbeiner is entering his second season at the helm of the Aggie women's basketball program. Overall, Finkbeiner has a 492-256 (.658) record in 24 years as a collegiate head coach at USU, Oral Roberts (1996-2012) and Southern Nazarene (1991-96). Utah State opens action on Tuesday, Nov. 5 in an exhibition against Northwest Nazerene at 7 p.m. The season officially begins on Saturday, Nov. 9 against Black Hills State at 7 p.m. at the Dee Glen Smith Spectrum. Aggie women's basketball tickets are available by contacting the USU Athletics Ticket Office at (435) 797-0305 or at 1-888-U-STATE-1 (1-888-878-2831) for more information or visit the Utah State athletics web site at www.UtahStateAggies.com. Fans can follow USU women's basketball at www.twitter.com/UtahStateWBB, as well as on facebook, at www.facebook.com/USUWBB. Aggie fans can also follow the Utah State athletic program at twitter.com/USUAthletics or on Facebook at facebook, at www.facebook.com/USUAthletics. Utah State women's basketball is also on instagram at www.instagram.com/USUWbasketball. 2013-14 Mountain West Women's Basketball Preseason Poll Rank Team (1st-place votes) Points 1. Fresno State (17) 238 2. Wyoming (4) 212 3. San Diego State (2) 196 4. New Mexico 185 5. UNLV (2) 170 6. Utah State 136 7. Colorado State 130 8. Boise State 96 9. San José State 76 10. Nevada 62 11. Air Force 28 |


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A statewide Silver Alert has been canceled. The missing Ogden man was spotted on the downtown trolley this morning.
It started as a typical morning for downtown trolley driver, Marilyn Bristel, but things changed. "One of my passengers, he was sitting right here with me and he was like, don't that guy look familiar, and I looked through the rear view mirror and I was like, you're right! And he says, that guy was on television last night."
"All I can say is I'm fine. And hopefully everything will come out just fine," Paul LeBeau said.
LeBeau would not explain why he left home.
Investigators said it may be an issue with his marriage. Details of the Silver Alert included that he may suffer from dementia or memory loss.
According to detectives, LeBeau was alert, and answered simple questions accurately.
Sheriff's deputies say LeBeau didn't want to go home. Since it couldn't be proved that he was mentally ill, he was returned to the shelter where he was staying.
LeBeau's wife, Michaela said she is concerned for her husband's safety and he was diagnosed with dementia ten years ago.


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The Observation Deck
A blog of opinions on local, state and national issues
Posts filtered on Category
Malaysia has a big PR problem
To restore confidence that it can find a missing airliner, Malaysian officials must appoint one credible representative to share all of their information, and stop linking the plane's disappearance to political opponents, says Joshua Kurlantzick in Bloomberg Businessweek.
[Read More]
News plus mystery = itch
When a news story breaks, such as a plane's disappearance, "I desire the sort of coverage that could fill the Indian Ocean," says Jack Shafer in Reuters. "Combine news of the weird with a mystery, such as an unaccountably missing airliner on the other side of the world, and you have the makings of an […]
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Long story short
Our opinions: We weigh in briefly on Rep. Chris Gibson's debt ceiling vote, Jet Blue, and a new push for a single payer proposal. Politics at play When a congressman criticizes his own party's leadership over passage of a "clean" debt ceiling bill, you can be sure politics are at play. U.S. Rep. Chris Gibson, […]
[Read More]
Deregulation's downside
Individuals and entire cities have been "left economically stranded" by the deregulation of the airline industry, says Lynn Stuart Parramore in AlterNet. "Increased competition without adequate regulation is not much better than monopoly conditions," she says.
[Read More]
Time for a flight check
Our opinion: Stopping the merger of American Airlines and US Air makes sense. With higher air fares and lesser service, where is the benefit to consumers in reduced competition? The U.S. Justice Department's move last week to block the merger of American Airlines and US Airways might have left investors grumbling, but it's potentially welcome […]
[Read More]
Asiana lawsuit won't fly
Erik Wemple of the Washington Post says Asiana Airlines' suit against a TV station that misreported the names of pilots in a crash invites the question, "Is the airline worse at PR, law or aviation?"
[Read More]
How to survive a plane crash
William McGee at CNN offers tips on how to improve your chances of walking away from a plane crash. McGee, author a book on aviation safety, advises passengers to stay alert during portions of the flight, and always pay attention to the safety briefing.
[Read More]
Reclining seats lead to decline in civility
The small comfort gained from reclining your seat is canceled by the passenger in front of you doing the same, says Dan Kois in Slate. Rather than hoping no one reclines for "the common good," the real issue is why airplane seats recline in the first place, he says.
[Read More]
Should airports have passenger advocates?
The latest idea in the ongoing debate over searches of passengers at airports: Official consumer advocates. The concept seemed to move forward Wednesday at a Senate Judiciary Committee oversight hearing, where Homeland Security Secretary Janet Napolitano endorsed Sen. Chuck Schumer's idea for passenger advocates in airports. Schumer, D-NY, and Sen. Susan Collins, R-Maine, have proposed […]
[Read More]
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FareSpotter >
City Guides > Bakersfield
Bakersfield: Home To Unique Traditions in Food and MusicBakersfield is perhaps best known as the birthplace of the "Bakersfield Sound", a music style that was introduced by such legendary artists as Buck Owens and Merle Haggard. At the Bakersfield Country Music Museum, the full and rich history of the music is on display. Another unique city tradition is Basque restaurants. A trip here is not complete without a visit to one of these traditional family style restaurants. Food is hearty, simple, and outstanding, and the Basque atmosphere is just as good." |


text: LI fights for hydro-electric power By: Claude Solnik June 30, 2010 Comments Off A stream of headlines about solar and wind projects may fill the news, reminding Long Islanders these sources of power are growing more popular. But with the sun and wind providing only about 2 percent of the state's power, New York's and Canada's rivers, lakes and waterfalls could prove at least an equally important source of ... Subscribe Login Email Address: Password: Already a paid subscriber but not registered for online access yet? For instructions on how to get premium web access, click here.Forgot your password? Print, Digital & Mobile1 Year$129 Digital & Mobile Only1 Month Intro Rate$2.99----------1 Year$99 Digital & Mobile Only1 Month Intro Rate$2.99----------1 Year$99 Print, Digital & Mobile1 Year$129 Print, Digital & Mobile1 Year$129----------Digital & Mobile Only1 Month Intro Rate$2.99----------1 Year$99 Share this:EmailPrintFacebookTwitterGoogle +1 hydropower Long Island Power Authority New York Power Authority upstate 7:17 am Wed, June 30, 2010 Long Island Business News Claude Solnik


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Type: | Trad, 1 pitch |
Consensus: | YDS: 5.0 French: 2- Ewbanks: 4 UIAA: I ZA: 6 British: MM 1c [details] |
FA: | unknown |
Page Views: | 545 |
Submitted By: | Guy H. on Dec 9, 2001 |
Climbing areas reopened after flood MORE INFO >>> |
Comments on East Face/Anomaly | Add Comment |
Show which comments —
By shad O'Neel May 1, 2003 |
The mid section of this rock has the most features and least moss. About half way up there is a wild dike that gives you some solid holds. A good approach route is from the end of Columbine St. Then head up towards Woods Quarry and scramble up the Regency first. Afterwards climb the Amoeboid, then finish with the grand traverse of Royal Arch. |
By Julius Beres From: Boulder, CO Jun 22, 2009 rating: 5.1 2 6 II 7 MD 2a |
I did this along with Amoeboid and The Royal Arch.... This one was the least pleasant. Perhaps the climbing wasn't any harder than 5.0, but there was so much moss and lichen on the rock. If you do this, definitely continue on Amoeboid. The hike down the south side is a bit of a bushwack, so you may as well do both.... |


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Sorbet fizz
Perfect for an after-dinner dessert or afternoon tea, this lemon meringue slice tastes as good as it looks.
To Prep |
To Cook |
AVG RATING (36 Members) |
Rocky road is a favourite treat for kids and adults alike. The best thing about this... Watch Video
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Very easy and tasty! Like others, I used Scotch Biscuits and didn't bother putting the coconut in the meringue. Took it to a BBQ and got rave reviews, definitely a keeper. Great tip below about putting the slice back in the fridge for 15mins after the lemon sauce added, so it was easy to spread the meringue on top.
OMG what a taste and texture sensation - so much nicer than Lemon Meringue Pie! The base was melt in the mouth, the curd nicely tart and the meringue light as a feather. Made these with my daughter yesterday - we added a little more lemon juice to the curd until it tasted just right and left out the coconut. Next time will use a bit more biscuit for the base and we did reduce the butter to 90 g as suggested by others - ours was really thin but other than that no change. Will definitely make again and again and again............
Absolutely beautiful! A hit in my family. The only difference I did was used scotch finger biscuits and due to other comments I decided to put 90g of butter in the base instead of 150 which was perfect. Has to set in fridge for a few hours before slicing and removing from tray. Made yesterday arvo and only 2 slices left! :( I need to make more! :)
I use scotch finger biscuits for the base. Always well received by guests and some leftover for me as hubby doesn't eat "lemon thinks".
Nice and easy to make, however like in all the other comments my base was crumbly and the coconut in the meringue was too much and kind of flattened it. I am going to make it again but with either the coconut mixed in the biscuit base (I used scotch finger) or sprinkled over the meringue before baking.
I made this exactly to the recipe and I found that 125gm butter way too much if using the macaroons, next time I will try it with another biscuit as other people have, but having said that we loved the other two layers
Yum Yum Yum!!! This is a winner! I made the base with scotch finger biscuits as the others are a bit hard to find. Took it to work today and everyone loved it. Hubby has 5 pieces left and is already asking me to make more. I forgot to put the coconut in the meringue, so sprinkled on top before putting in the oven, this worked really well and went nice and brown and crispy.
Delicious slice, made to the recipe, only changing the base, used a packet of Marie biscuits (250g) and topped up with coconut, yes the base is a little crumbly but is better the next day after being in the fridge - beautiful as afternoon tea or dessert and not too sweet !
I make this with a plain biscuit base and leave out the coconut in the meringue. It's always popular. Best made on the day of serving as the meringue does not keep well.
This was very yummy!! The lemony section is sweet and not too tart - the meringue with coconut tastes awesome. I didn't have any macaroons at hand - and I couldn't find any pre-made ones at the shop - so I used Arnotts Marie biscuits and added a little coconut to the mix. It came out a little crumbly, but tasted good!!
This was a very easy to follow recipe. I had a lot of trouble finding the macaroons so I used a mix of scotch fingers and coles anazac cookies. I also reduced the amount of butter. This made a beautiful base. They came out tasting amazing. I would highly recommend this recipe to others. YUM!
Wonderful slice. Love it!!
Just like grandma used to make! So yummy, and pretty quick to put together.
Like the last review I found the base to be very crumbly. I love the taste however, so my advice is to blind bake the base then add the lemon filling, place in the fridge for 10 mins or so, then add the meringue. That stops the lemon and the meringue becoming mixed and would also fix the issue of the base falling apart. I'll definitely make this again, everyone in my office loved it.
Yum-o this was so easy to make the base a bit crumbly will try a different base next time cant wait to make it again
This recipe is very popular with family and friends - always getting requests to make it. I use a mix of dessicated and shredded coconut for the meringue top to give it a bit more texture. So easy and delicious.
Very nice. I didn't use the macaroons, I used the Raspberry Coconut Slice base (thick pastry base) and that worked beautifully. I also used 1/2 a cup of coconut in the meringue, and refrigerated the lemon for half an hour before spreading the meringue and it spread easily.
The meringue thingy was a bit tricky but the kids loved it
Yum!! Everybody loved this slice! I used scotch finger biscuits for the base and added 1/4 cup desiccated coconut to substitute the coconut macaroon biscuits.
This was amazing....I did use the coconut macroons in the base. Could only find the Safeway/Woolworths Select brand moist Coconut Macroons. I was concerned at first that there was too much butter to macroon, and I still may try gradually reducing the quantity of butter, but the end result was great. I think I would keep using the macroons as the flavour wtih the rest of the slice was delicious, and a great soft delicate texture.I probably only used 3/4 cup of dessicated coconut in the meringue. Got so many compliments on this slice. Will definately make again, true to the recipe except for the slight reductions in butter and coconut. Highly recommend
Got great compliments about this slice and it was really easy to make. I used scotch fingers for the base as they were much cheaper and I only used about 1 cup of coconut in the meringue. Will definitely be making this again and again
This was a big hit both at home and at work. I replaced the coconut macaroon biscuits with Butternut Snap biscuits which made for a lovely crunchy base. I'm going to try using Chocolate Ripple biscuits for the base, and drizzle a layer of chocolate between base & lemon mixture for an extra chocolatey taste. Thank you reillyoz007 for the tip on refrigerating between lemon mixture and adding meringue - pure genius!
Very simple and VERY tasty.
I made this for our bible study group and everyone loved it. I did not add any coconut to the recipe at all and used scotch finger biscuits for the base. Aldi's scotch finger biscuits taste exactly the same as Arnott's and they are half the price.
This is great. The recipe is easy and very forgiving. I've used the Scotch Finger biscuits per a previous poster and also Nice biscuits with a handful of oats to make up the weight. Next time I think I'll add some extra zest to the base as we're into lemon in this family. Refrigerate the biscuit base for 15 minutes then top with the lemon mixture and refrigerate another 15 minutes. This sets it a bit so the meringue spreads easily.
Ditto on the scotch fingers for the base...only had one drama...how to spread the meringue over the lemon without it all getting mixed in together.
absolutely delicious, everyone enjoyed this tasty treat. i used just half a cup of coconut in the meringue and it worked well. will definately make again.
I also made this without the coconut in the meringue. Thanks emmaandmark for the tip to use scotch finger biscuits in the base- couldn't find the other ones!!! This was my first time making meringue and it turned out fantastic. My favorite so far!!! Definately making it again soon.
the whole family loved it
Delicious. Everyone loved it. Nice and easy to make too.
Great recipe! My family can hardly wait for it to cool down before they eat it. Although i've found that less butter in the base works better.
Great recipe, I did not use coconut in it, and it tasted fantastic. I also used scotch finger biscuits as base rather than macaroons.
I've made this without the coconut in the meringue and it is absolutely delicious.
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Ooooh it looks beautiful. May I ask where you got your Etalon nib from?
Now I have to have one
From a pen I had in my collection which had a leaky section. On that pen I replaced the complete section with a new one obtained from Dutchpen so had the medium nib spare. You might try Dutchpen for a nib only. He had some for sale a few months ago.


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"Location, Location, Location! It was truly like staying "home away from home". Perfect – the Innkeepers are wonderful, the staff is delightful. Breakfast is yummy! We will be back!"
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Free Family Art day at the McNay Art Museum in San Antonio, Texas on Sunday Nov. 3rd, 2012.
Celebrating Día de los Muertos, (Day of the Dead in San Antonio) SAY Sí's 6th Annual Muertitos Fest provides a comprehensive perspective of the significant cultural holiday and will feature local artists, folk art exhibits, altars to honor the deceased, family art workshops, food booths, artisan stalls, live music and dance performances on November 1-3, 2012.


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Maria Sharapova has injured her right collarbone and decided to withdraw from the Brisbane International as a precaution ahead of the Australian Open.
The French Open champion pulled out of the Brisbane tournament on Tuesday after feeling pain while practicing before her opening match.
"I still have quite a bit of time to prepare for Australia. I'm on the right track, been training really well, so I just don't want to jeopardize what I've gained in the offseason so far," the No. 2-ranked Sharapova said. "Just have to make a smart move here."
The 25-year-old Russian also withdrew from the Brisbane International last year because of injury but recovered quickly to reach the Australian Open final, where she lost in straight sets to Victoria Azarenka.
She said the latest injury also forced her to withdraw from a recent exhibition tournament in South Korea, but was "not at all" related to the right shoulder problem which has plagued her since 2008.
"I had a bit of inflammation in my collarbone, and I sent (scan results) to a doctor in New York and he told me I couldn't really do much overhead training for about a week," she said. "So to be fair, I haven't really given myself a chance to pretty much hit any serves or anything over my head ... So I just kind of ran out of time here." she said.
Sharapova said she'd started practicing her serves again on Monday and it wasn't enough time to properly prepare for a tournament featuring eight of the top 10 women. The Australian Open starts Jan. 14 at Melbourne Park.
The four-time major winner told a news conference earlier in the Brisbane tournament that she felt relaxed and relieved to have finally broken a Grand Slam drought by winning the French Open last year. The win at Roland Garros completed a career Grand Slam and was her first major title since the 2008 Australian Open.
On Tuesday, she reiterated she was "feeling so much better."
"I just don't want to jeopardize what I've built on," she said, adding that her decision to skip the 2012 Brisbane tournament was a good example of putting her health ahead of match practice.
"It's kind of the way that I've always built my career around the fact that it's very important for me to go into something like the Australian Open believing and knowing that I'm healthy, that I'm confident.
"I don't exactly need to play five tournaments in order to feel that way." she added.
Sharapova's absence gives Australia's Jarmila Gajdosova a direct route to the quarterfinals, where she'll meet Slovakian veteran Daniela Hantuchova.
Keywords: Maria Sharapova, Brisbane International, Australian Open


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It appears as if the long battle to save the local VA hospital is over.
President Obama signed the $70 million authorization to renovate parts of the Jonathan M. Wainwright Memorial VA Medical Center and to build a new 66,000-square-foot outpatient clinic on the grounds.
This project means the Department of Veterans Affairs will continue to have a major presence in this community for decades to come. That is good for the local economy, and — more importantly — it means thousands of veterans throughout Southeastern Washington, Northeastern Oregon and Idaho will continue to have access to the quality medical care they've earned.
The VA under several presidents has made moves to close the Wainwright facility and force veterans to Spokane, Portland or Seattle for care. We have thought that approach was wrong.
So, too, have our elected representatives in Congress, Democrats and Republicans. The U.S. representatives from the 5th Congressional District — Former House Speaker Tom Foley, former Rep. George Nethercutt and Rep. Cathy McMorris Rodgers — have worked with Sen. Patty Murray to put pressure on the VA to do the right thing.
More than 22 years ago the top officials at what was then called the U.S. Veterans Administration were intent on closing Walla Walla's VA medical center.
Foley, who was then House majority leader, used his considerable political muscle to push through a prohibition against downgrading the Walla Walla medical center from a full-service hospital.
In 2004, VA officials once again put Wainwright in the cross hairs. This time is was Murray, a member of the Veterans Affairs Committee, who used her political clout. She held a committee hearing in Walla Walla on the potential closure.
Murray was able to get a reprieve and over the past five years there's been ups and downs in the struggle to get a clear victory that would ensure a continued presence in Walla Walla. Murray joined forces with Nethercutt and then McMorris Rodgers, as well as her Senate colleague Maria Cantwell, to hold VA officials accountable.
Three years ago it was announced a four-story clinic was to be built on the local VA grounds, but those plans didn't have any dollars behind them.
Last week's authorization of those funds makes it almost a certainty the clinic will come to fruition. It's all a clear signal that the VA will continue to have a presence in this region and this community. This good news is welcome in the wake of the current turmoil over the possible loss of jobs at the penitentiary.
Even so, our elected officials and community leaders can't rest with this victory. The VA grounds have the potential to house even more services for veterans.
But for now we are pleased that $70 million has been authorized and construction will begin at the Walla Walla facility.
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