SH2 domain

Pfam_box
Symbol = SH2
Name =

The Src homology 2 domain (or SH2 domain) is a protein domain of about 100 amino acid residues first identified as a conserved sequence region among the oncoproteins Src and Fps.

Similar sequences were later found in many other intracellular proteins involved in signal transduction, such as Abl, ZAP70, STAT proteins, Grb2 and RasGAP.

Binding and phosphorylation

SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target protein, and SH2 domains represent the largest class of known pTyr-recognition domains [Pawson, T., Gish, G., Nash, P. (2001). SH2 domains, interaction modules and cellular wiring. Trends in Cell Biology 11(12): 504-511.] .

Phosphorylation of tyrosine residues in a protein occurs during signal transduction and is carried out by tyrosine kinases. In this way, phosphorylation of a substrate by tyrosine kinases acts as a switch to trigger binding to an SH2 domain-containing protein. The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.

Diversity

SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum [Eichinger, L. et al. (2005). The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43-57.] .

A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 110 proteins encoded by the human genome [Liu et al. (2006), The Human and Mouse Complement of SH2 Domain Proteins – establishing the boundaries of phosphotyrosine signaling. Molecular Cell 22: 851-868.] , representing a rapid rate of evolutionary expansion among the SH2 domains.

A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice. [ [http://sh2.uchicago.edu/ the SH2 domain ] ]

Proteins with SH2 domains include:
*Abl
*GRB2
*RasGAP
*STAT proteins
*ZAP70
*SHP2
*PI3K
*Phospholipase C γ form
*CRK
*SOCS
*Src

Functions

Many biological signaling proteins use this mode of regulated protein-protein interactions as a means to localize proteins to various sub-cellular compartments, control enzymatic activities of proteins as well as nucleate multiprotein complexes, to name a few.

The SH2 domain has thus become a prototype for a large number of modular interaction domains that have been since identified.

The discovery of the SH2 domain and its many roles in signal transduction introduced the critical concept of how biology has exploited the use of modular interaction domains to create complex signaling networks.

Human proteins containing this domain

ABL1; ABL2; BCAR3; BLK; BLNK; BMX; BTK; CHN1;
CHN2; CISH; CRK; CRKL; CSK; DAPP1; FER; FES;
FGR; FRK; FYN; GRAP; GRAP2; GRB10; GRB14; GRB2;
GRB7; GRID; HCK; HSH2D; INPP5D; INPPL1; ITK; JAK2;
LCK; LCP2; LYN; MATK; NCK1; NCK2; PIK3R1; PIK3R2;
PIK3R3; PLCG1; PLCG2; PTK6; PTPN11; PTPN6; RASA1; SH2B;
SH2B1; SH2B2; SH2B3; SH2D1A; SH2D1B; SH2D2A; SH2D3A; SH2D3C;
SH2D4A; SH2D4B; SH2D5; SH2D6; SH3BP2; SHB; SHC1; SHC3;
SHC4; SHD; SHE; SLA; SLA2; SOCS1; SOCS2; SOCS3;
SOCS4; SOCS5; SOCS6; SOCS7; SRC; SRMS; STAT1; STAT2;
STAT3; STAT4; STAT5A; STAT5B; STAT6; SUPT6H; SYK; TEC;
TENC1; TNS; TNS1; TNS3; TNS4; TXK; VAV1; VAV2;
VAV3; YES1; ZAP70;

References

5. Huang H, Li L et al. (2008) Defining the Specificity Space of the Human Src Homology 2 Domain. Mol Cell Proteomics. 7:768-84.

External links

* [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=sh2 Entry for the SH2 domain in the SMART database]
* [http://nashlab.uchicago.edu/domains/phospho-tyr-binding/sh2-domain.html Nash Lab: SH2 domain]
* [http://pawsonlab.mshri.on.ca/index.php?option=com_content&task=view&Itemid=64&id=178 Pawson Lab: SH2 domain]
* [http://scop.mrc-lmb.cam.ac.uk/scop/data/scop.b.e.bfd.b.A.html List of SH2 domain proteins in SCOP database]
* [http://genetics.uchc.edu/faculty/mayer_linkpage.htm Mayer Lab SH2 Domain Database]
* [http://lilab.uwo.ca/SMALI.htm Li lab: SMALI ─ SH2 Domain-binding Peptide Prediction]

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