of EGFR on tyrosine 1068, likely because of reduced plasma-membrane associated PTPkappa expression and hence reduced PTPkappa-mediated dephosphorylation of its membrane associated substrates, such as EGFR. Structure PTPkappa possesses an extracellular region, a single transmembrane region, and two tandem catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. PTPkappa is a member of the R2B subfamily of RPTPs, which includes RPTPM, RPTPT, and RPTPU. PTPkappa shares most sequence similarity with PTPmu and PTPrho. Crystal structure analysis of the first phosphatase domain of PTPkappa demonstrates that it shares many conformational features with PTPmu, including an unhindered open conformation for the catalytically important WPD loop, and a phosphate binding loop for the active-site cysteine (Cys1083). PTPkappa exists as a monomer in solution, with the caveat that dimers of PTPkappa are observed depending on the nature of the buffer used. Alternative splicing Alternative splicing of exons 16, 17a, and 20a has been described for PTPRK. Two novel forms of PTPRK were identified from mouse full-length cDNA sequences and were predicted to result in two PTPkappa splice variants: a secreted form of PTPkappa and a membrane tethered form. Homophilic binding PTPkappa mediates homophilic cell-cell aggregation via its extracellular domain. PTPkappa only mediates binding between cells expressing PTPkappa (i.e. homophilic), and will not mediate cell aggregation between cells expressing PTPkappa, PTPmu or PTPrho (i.e. heterophilic). Regulation Proteolysis and N-glycosylation Full-length PTPkappa protein is cleaved by furin to generate two cleaved fragments that remain associated at the plasma membrane, an extracellular (E) subunit and an intracellular phosphatase (P) subunit. In response to high cell density or calcium influx following trifluoperazine (TFP) stimulation, PTPkappa is further cleaved by ADAM 10 to yield a shed extracellular fragment and a membrane tethered intracellular fragment, PΔE. The membrane tethered PΔE fragment is further cleaved by the gamma secretase complex to yield a membrane-released fragment, PIC, that can translocate to the cellular nucleus, where it is catalytically active. Glycosylation of the extracellular domain of PTPkappa was demonstrated to occur preferentially in WiDr colon cancer cells that over-express N-acetylglucosaminyl transferase V (GnT-V). Over-expression of GnT-V in these cells increased the cleavage and shedding of PTPkappa ectodomain and increased migration of WiDr cells in transwell assays. As a result of glycosylation of PTPkappa by GnT-V, EGFR was phosphorylated on tyrosine 1068 and activated, and