Tyrosine phosphorylated motifs

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

In B lymphocytes, coupling of the antigen receptors to Erk MAPkinase is protein tyrosine kinase (PTK)-dependent (Pao et al, 1997). Following ligation of the BCR (Fig. 19.2) the PTK, Lyn, tyrosine phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the accessory transducing molecules Ig-a and Ig-(3, leading to the recruitment... 

SHIPl (hereafter SHIP) was identified in the early 1990s as a 145 kDa intracellular protein that is tyrosine phosphorylated upon the stimulation of hemeatopoietic cells via B and T-cell receptor, and by multiple cytokines (Damen et al, 1996, Lioubin et al. 1996). Molecular cloning of cDNA for SHP revealed that the molecule consists of an N terminal SH2 domain, a highly conserved, centrally located motif having Ptdins 5-phosphatase activity, two NPXY sequmces, which are phosphorylated on Tyr upon various stimuli and a proline-rich C terminus (Figure 2). SHIP hydrolyses PtdIns(3,4,5)/ 3, and inositol 1,3,4,5-tetrakisphosphate both in vitro and in vivo, thus belongs to the type n 5-phosphatases, charactaized also by their... 

Finally, platelets can be activated by immune complexes following binding of immunoglobulin G (IgG) Fc domains to platelet Fey RII. This process involves tyrosine phosphorylation of a motif designated as ITAM (immunoreceptor tyrosine-based motif) found on the cytoplasmic domain of platelet Fey RII receptors (73). This may play a role in immune complex diseases, particularly in heparin-induced thrombocytopenia. 

Phosphotyrosine phosphatases are integrated just like tyrosine Idnases into signalling pathways. They interact with receptors and have recognition motifs that direct diem to their targets. 5 Protein phosphotyrosine phosphatases downregulate tyrosine phosphorylation and play a role in cellular regulation as important as that of protein tyrosine kinases. 

Signaling proteins form complexes with other molecules using conserved motifs or domains, which are modular in the sense that the domain by itself typically is sufficient for its function (7, 8). Protein-protein interaction domains include those responsible for binding to phosphorylated receptors and other tyrosine-phosphorylated proteins (Src homology 2 and phospho-tyrosine binding domains) or to proline-rich protein... 

Syk assembles into signalling complex via interaction between its tandem Src biology 2 (SH2) domains and the tyrosine-phosphorylated immuno receptor tyrosine-based activation motif (ITAM) present in the FcRy. The FcRy and Syk are essential for activation of mouse platelets by collagen . 

Margolis B, Hu P, Katzav S, Li W, Olivhi JM, Ullrich A, Weiss A, Schlessingsi J. Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs Nature 356 71-74,1992. 

The first evidence of a cellular substrate of the insulin receptor kinase came from White et al. (1985b) who described a 185 kDa phosphoprotein in Fao hepatoma cells which was rapidly phosphorylated upon insulin stimulation. ppl85, recently renamed IRS-1, is a cytosolic protein with at least 30 potential serine/threonine- and 10 potential tyrosine-phosphorylation sites (Sun et al., 1991). Six of these tyrosine-phosphorylation sites lie in the amino acid sequence motif Tyr-Met-Xaa-Met which is recognized in its phosphorylated form by the SH2 (src homology 2) domain of the phosphatidylinositol 3-kinase (PI 3-kinase) (Sun et al., 1991). 

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