molecules involved in cell signaling, most commonly by binding to activating receptors including TCRs, BCRs and FcRs. Subsequently, phospholipase Cy and phosphatidylinositol 3-kinase (PLCy and PI3-K) are activated, together leading to the production of phosphoinositol messengers and increase in cytoplasmic Ca2+. SHIP Several ITIM-bearing receptors bind SHIP, including FcγRIIB. SHIP is a 5' inositol phosphatase that is expressed in most hematopoietic cells. It plays an important regulatory role in the immune system. SHIP consists of an N-terminal SH2 domain, a catalytic domain and a C-terminal tail that contains two phosphorylation sites. There are several isoforms of SHIP and the expression of these isoforms differs among different cell types.. In addition, another SHIP gene, SHIP-2, has been identified. SHIP-2 is also expressed in non-hematopoietic cells. The binding of SHIP to ITIM-bearing receptors is mediated by the SH2 domain. There are several mechanisms by which SHIP can inhibit cell activation. These can be divided into mechanisms that involve the catalytic activity of SHIP and mechanisms that involve interactions of other molecules with the C-terminal part of SHIP. SHP Many ITIM-bearing receptors recruit SHP-1 and/or SHP-2 including KIRs, ILT, Ly49, LAIR-1, CD22, CD72 and Signal Regulatory Protein SIRPα. SHP-1 and SHP-2 are structurally related protein tyrosine phosphatases but have different expression patterns and biological functions. SHP-1 is expressed in hematopoietic cells and at lower levels in epithelial cells. Like SHIP, SHP-1 is involved in the negative regulation of cell activation following a variety of stimuli such as growth factors, cytokines, integrin signaling and antigen receptor signaling. SHP-2 is ubiquitously expressed and is considered a positive regulator of cytokine and growth factor receptor signaling. SHP-1 and SHP-2 consist of two SH-2 domains, a catalytic domain and a C-terminal tail. The N-terminal SH2 domain is involved in an auto-inhibitory mechanism, as removal of this domain activates the phosphatase. Recruitment of either SHIP or SHP-1 by ITIM-bearing receptors has different outcomes: recruitment of SHP-1 abrogates tyrosine phosphorylation of signaling molecules that would occur upon triggering of an ITAM-bearing receptor, while SHIP recruitment does not affect the initial phosphorylation, but interferes with the recruitment of downstream effectors to the site of cell activation. ITIMs can also work in conjunction with Immunoreceptor tyrosine-based switch motifs(ITSM) in order to activate ITIM-bearing receptors such as SHP-2. Negative vs. positive signaling of ITIM motifs Even if the most receptors containing ITIM are considered to have inhibitory effects on signaling pathways of