Src homology

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. 

Tyrosine phosphorylated IRS interacts with and activates PI 3-kinase [3]. Binding takes place via the SRC homology 2 (SH2) domain of the PI 3-kinase regulatory subunit. The resulting complex consisting of INSR, IRS, and PI 3-kinase facilitates interaction of the activated PI 3-kinase catalytic subunit with the phospholipid substrates in the plasma membrane. Generation of PI 3-phosphates in the plasma membrane reemits phospholipid dependent kinases (PDKl and PDK2) which subsequently phosphorylate and activate the serine/threonine kinase Akt (synonym protein... 

All PLC isozymes have conserved catalytic domains designated X and Y, and a C2 domain similar to that in cPLA2 (Fig. 2). In addition, the (3, y and 8 isozymes have pleckstrin homology (PH) domains and EF-hand domains located in theN-teiminal region. The y isozymes differ in that they have Src homology domains (SH2 and SH3) and an additional PH domain split by the SH domains. The (3 and y isozymes are of140-155 kDa mass, whereas the 8 isozymes are smaller (85 kDa) and the o isozyme is larger (240 kDa). 

The Src homology 2 domain (or SH2-domain) is a protein domain of about 100 amino acid residues first identified in the tyrosine kinase Src. SH2-domain... 

The Src homology 3 domain is a 60 amino acid long domain that binds to proline-rich sequences, thereby enabling protein-protein interactions. 

The Src-homology 2 (SH2) domain is a protein domain of roughly 100 amino acids found in many signaling molecules. It binds to phosphorylated tyrosines, in particular peptide sequences on activated receptor tyrosine kinases or docking proteins. By recognizing specific phosphorylated tyrosines, these small domains serve as modules that enable the proteins that contain them to bind to activated receptor tyrosine kinases or other intracellular signaling proteins that have been transiently phosphorylated on tyrosines. 

SH1 Src homology 1 domain, Kinase domain Kinase activity... 

SH2 Src homology 2 domain Binding to phosphorylated tyrosine residues... 

SH3 Src homology 3 domain Binding to prolin-rich sequences... 

IL-10 inhibits CD28 and ICOS costimulations of T 127 cells via Src homology 2 domain-containing protein tyrosine phosphatase 1. J Allergy Chn Immunol 2007 120 76-83. 

JT. Kim YK. Zhu Z Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to 128 a spontaneous allergic inflammation in the murine lung. J Allergy Clin Immunol 2007 19 123-131. 

Src Homology-2 Domains and Structure-Based, Small-Molecule Library Approaches to Drug Discovery... 

Luther M, Rusnak D, Sternbach DD, Mehrotra M, Peel M, Shampine L, Davis R, Robbins J, Patel IR, Kassel D, Burkhart W, Moyer M, Bradshaw T, Berman J. Peptide inhibitors of Src SH3-SH2-phosphoprotein interactions. J Biol Chem 1994 269 31711-31719. Also, for pTyr mimics see Ye B, Akamatsu M, Shoelson SE, Wolf G, Giorgetti-Peraldi S, Yan X, Roller PP, Burke TR Jr. L-0-(2-Malonyl)tyrosine a new phosphotyrosyl mimetic for the preparation of Src homology 2 domain inhibitory peptides. J Med Chem 1995 38 4270-4275. 

Eck MJ, Shoelson SE, Harrison SC. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature 1993 362 87-91. 

Many non-receptor tyrosine kinases have been identified as products of retrovirally encoded oncogenes. Non-receptor tyrosine kinases can be divided into two groups transmembrane and cytosolic families. The c-src tyrosine kinase is the prototype of the cytosolic tyrosine kinases. Regions within these non-receptor tyrosine kinases share homology with the Src kinase, known as Src homology 2 and 3 (SH2 and SH3) domains, and mediate protein-protein interactions between the receptor tyrosine kinases and the intracellular targets (reviewed in Cantley et al., 1991 Pawson and Gish, 1992 Mayer and Baltimore, 1993). 

New developments in immobilization surfaces have lead to the use of SPR biosensors to monitor protein interactions with lipid surfaces and membrane-associated proteins. Commercially available (BIACORE) hydrophobic and lipophilic sensor surfaces have been designed to create stable membrane surfaces. It has been shown that the hydrophobic sensor surface can be used to form a lipid monolayer (Evans and MacKenzie, 1999). This monolayer surface can be used to monitor protein-lipid interactions. For example, a biosensor was used to examine binding of Src homology 2 domain to phosphoinositides within phospholipid bilayers (Surdo et al., 1999). In addition, a lipophilic sensor surface can be used to capture liposomes and form a lipid bilayer resembling a biological membrane. 

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