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MeSH Review

src Homology Domains

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Disease relevance of src Homology Domains


High impact information on src Homology Domains

  • NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion [6].
  • Mutations that inactivate the SRC homology 2 (SH2) domain, the GRB2-binding site in BCR, or the major autophosphorylation site of the kinase domain selectively disrupt downstream signaling but not tyrosine kinase activity [7].
  • Src homology 2 (SH2) domains on the regulatory subunit of phosphoinositide 3-kinase (PI 3-kinase) mediate its binding to specific tyrosine-phosphorylated proteins in stimulated cells [8].
  • Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins [8].
  • Signaling by tyrosine kinase receptors is mediated by selective interactions between individual Src homology 2 (SH2) domains of cytoplasmic effectors and specific phosphotyrosine residues in the activated receptor [9].

Chemical compound and disease context of src Homology Domains

  • We investigated the functionality of the Jak1 SH2 domain by stably reconstituting Jak1-defective human fibrosarcoma cells U4C with endogenous amounts of Jak1 in which the crucial arginine residue Arg466 within the SH2 domain has been replaced by lysine [10].
  • The Src homology 3 (SH3) domain from the c-Crk-I adaptor protein has been labeled with a Trp analogue, 7-azatryptophan (7AW), using Escherichia coli Trp auxotrophs [11].
  • Unexpectedly, however, the interaction of SIV Nef with human Lck or Hck is not mediated via its consensus proline motif, which is known to mediate HIV-1 Nef binding to Src homology 3 (SH3) domains, and various experimental analyses failed to show significant interaction of SIV Nef with the SH3 domain of either kinase [12].
  • The large (130kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer [13].

Biological context of src Homology Domains


Anatomical context of src Homology Domains

  • p56lck, a member of the src family of protein tyrosine kinases, is an essential component in T cell receptor (TCR) signal transduction. p56lck contains a src homology 2 (SH2) domain found in a number of proteins involved in intracellular signaling [19].
  • Src homology 3 (SH3) domains have been suggested to play an important role in the assembly of the superoxide-forming nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upon activation of phagocytes, which involves the association of membrane-bound and cytosolic components [20].
  • We suggest that the binding of an SH3 domain of p47-phox to p22-phox, and thus activation of the oxidase, does not occur in the neutrophils of this patient, although under artificial conditions, electron flow from NADPH to oxygen in cytochrome b558 is possible [20].
  • The dramatic effects of the SH3 domain of endophilin led us to propose a model for the temporal order of addition of endophilin and its binding partner synaptojanin in the coated vesicle cycle [21].
  • We show here that in human breast carcinoma cell lines, the SRC SH2 domain binds to activated epidermal growth factor receptor (EGFR) and p185HER2/neu [22].

Associations of src Homology Domains with chemical compounds

  • The beta sheets are highly similar to corresponding regions in the SH3 domain of the tyrosine kinase Src, even though the sequence identity of the two domains is low [23].
  • The Src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), SHP-2 and SH2-containing inositol phosphatase (SHIP) bound to this motif in a caspase-independent but cell-dependent manner [24].
  • Vav contains an array of structural motifs that include Src-homology domains SH2/SH3 and regions of homology to the guanine-nucleotide-exchange protein Dbl, pleckstrin and protein kinase C (refs 5-9) [25].
  • Recruitment and activation of PI(3)K by ligand-bound ER alpha are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85alpha, and extend to other steroid hormone receptors [26].
  • The peptide orientation is determined by a salt bridge formed by the terminal arginine residues of the ligands and the conserved aspartate-99 of the SH3 domain [27].

Gene context of src Homology Domains

  • A cDNA clone encoding a novel, widely expressed protein (called growth factor receptor-bound protein 2 or GRB2) containing one src homology 2 (SH2) domain and two SH3 domains was isolated [28].
  • The Fyn-large MAG association requires amino-terminal domains of Fyn that include SH2 and SH3 (Src homology domains 2 and 3) [29].
  • Thus, Src family kinases and proteins associating with their SH2 domains are required for entry into mitosis [30].
  • Alternatively, Pbs2p was activated by a mechanism that involves the binding of its amino terminal proline-rich motif to the Src homology 3 (SH3) domain of a putative transmembrane osmosensor Sho1p [31].
  • We previously identified a putative signal transducing adaptor molecule, named STAM, that contains an Src homology 3 (SH3) domain and immunoreceptor tyrosine-based activation motif (ITAM) [32].

Analytical, diagnostic and therapeutic context of src Homology Domains


  1. Identification of Src, Fyn, Lyn, PI3K and Abl SH3 domain ligands using phage display libraries. Rickles, R.J., Botfield, M.C., Weng, Z., Taylor, J.A., Green, O.M., Brugge, J.S., Zoller, M.J. EMBO J. (1994) [Pubmed]
  2. The SH2 domain of P210BCR/ABL is not required for the transformation of hematopoietic factor-dependent cells. Ilaria, R.L., Van Etten, R.A. Blood (1995) [Pubmed]
  3. A limited set of SH2 domains binds BCR through a high-affinity phosphotyrosine-independent interaction. Muller, A.J., Pendergast, A.M., Havlik, M.H., Puil, L., Pawson, T., Witte, O.N. Mol. Cell. Biol. (1992) [Pubmed]
  4. Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein. Pandey, P., Kharbanda, S., Kufe, D. Cancer Res. (1995) [Pubmed]
  5. Characterization of protein tyrosine phosphatase SH-PTP2. Study of phosphopeptide substrates and possible regulatory role of SH2 domains. Dechert, U., Adam, M., Harder, K.W., Clark-Lewis, I., Jirik, F. J. Biol. Chem. (1994) [Pubmed]
  6. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Mollet, G., Salomon, R., Gribouval, O., Silbermann, F., Bacq, D., Landthaler, G., Milford, D., Nayir, A., Rizzoni, G., Antignac, C., Saunier, S. Nat. Genet. (2002) [Pubmed]
  7. Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Goga, A., McLaughlin, J., Afar, D.E., Saffran, D.C., Witte, O.N. Cell (1995) [Pubmed]
  8. Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins. Rameh, L.E., Chen, C.S., Cantley, L.C. Cell (1995) [Pubmed]
  9. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Zonca, P., Giordano, S., Graziani, A., Panayotou, G., Comoglio, P.M. Cell (1994) [Pubmed]
  10. The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression. Radtke, S., Haan, S., Jörissen, A., Hermanns, H.M., Diefenbach, S., Smyczek, T., Schmitz-Vandeleur, H., Heinrich, P.C., Behrmann, I., Haan, C. J. Biol. Chem. (2005) [Pubmed]
  11. Domain-specific incorporation of noninvasive optical probes into recombinant proteins. Muralidharan, V., Cho, J., Trester-Zedlitz, M., Kowalik, L., Chait, B.T., Raleigh, D.P., Muir, T.W. J. Am. Chem. Soc. (2004) [Pubmed]
  12. Simian immunodeficiency virus and human immunodeficiency virus type 1 nef proteins show distinct patterns and mechanisms of Src kinase activation. Greenway, A.L., Dutartre, H., Allen, K., McPhee, D.A., Olive, D., Collette, Y. J. Virol. (1999) [Pubmed]
  13. Organization of functional domains in the docking protein p130Cas. Nasertorabi, F., Garcia-Guzman, M., Briknarová, K., Larsen, E., Havert, M.L., Vuori, K., Ely, K.R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  14. Direct demonstration of an intramolecular SH2-phosphotyrosine interaction in the Crk protein. Rosen, M.K., Yamazaki, T., Gish, G.D., Kay, C.M., Pawson, T., Kay, L.E. Nature (1995) [Pubmed]
  15. Solution structure of the SH3 domain of Src and identification of its ligand-binding site. Yu, H., Rosen, M.K., Shin, T.B., Seidel-Dugan, C., Brugge, J.S., Schreiber, S.L. Science (1992) [Pubmed]
  16. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Stoyanov, B., Volinia, S., Hanck, T., Rubio, I., Loubtchenkov, M., Malek, D., Stoyanova, S., Vanhaesebroeck, B., Dhand, R., Nürnberg, B. Science (1995) [Pubmed]
  17. Differential complementation of Bcr-Abl point mutants with c-Myc. Afar, D.E., Goga, A., McLaughlin, J., Witte, O.N., Sawyers, C.L. Science (1994) [Pubmed]
  18. Synaptic vesicle endocytosis impaired by disruption of dynamin-SH3 domain interactions. Shupliakov, O., Löw, P., Grabs, D., Gad, H., Chen, H., David, C., Takei, K., De Camilli, P., Brodin, L. Science (1997) [Pubmed]
  19. p56lck interacts via its src homology 2 domain with the ZAP-70 kinase. Duplay, P., Thome, M., Hervé, F., Acuto, O. J. Exp. Med. (1994) [Pubmed]
  20. 156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox. Leusen, J.H., Bolscher, B.G., Hilarius, P.M., Weening, R.S., Kaulfersch, W., Seger, R.A., Roos, D., Verhoeven, A.J. J. Exp. Med. (1994) [Pubmed]
  21. The role of dynamin and its binding partners in coated pit invagination and scission. Hill, E., van Der Kaay, J., Downes, C.P., Smythe, E. J. Cell Biol. (2001) [Pubmed]
  22. Involvement of pp60c-src with two major signaling pathways in human breast cancer. Luttrell, D.K., Lee, A., Lansing, T.J., Crosby, R.M., Jung, K.D., Willard, D., Luther, M., Rodriguez, M., Berman, J., Gilmer, T.M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  23. Structure of the PI3K SH3 domain and analysis of the SH3 family. Koyama, S., Yu, H., Dalgarno, D.C., Shin, T.B., Zydowsky, L.D., Schreiber, S.L. Cell (1993) [Pubmed]
  24. Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils. Daigle, I., Yousefi, S., Colonna, M., Green, D.R., Simon, H.U. Nat. Med. (2002) [Pubmed]
  25. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Tarakhovsky, A., Turner, M., Schaal, S., Mee, P.J., Duddy, L.P., Rajewsky, K., Tybulewicz, V.L. Nature (1995) [Pubmed]
  26. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Simoncini, T., Hafezi-Moghadam, A., Brazil, D.P., Ley, K., Chin, W.W., Liao, J.K. Nature (2000) [Pubmed]
  27. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Feng, S., Chen, J.K., Yu, H., Simon, J.A., Schreiber, S.L. Science (1994) [Pubmed]
  28. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Lowenstein, E.J., Daly, R.J., Batzer, A.G., Li, W., Margolis, B., Lammers, R., Ullrich, A., Skolnik, E.Y., Bar-Sagi, D., Schlessinger, J. Cell (1992) [Pubmed]
  29. Initial events of myelination involve Fyn tyrosine kinase signalling. Umemori, H., Sato, S., Yagi, T., Aizawa, S., Yamamoto, T. Nature (1994) [Pubmed]
  30. Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Roche, S., Fumagalli, S., Courtneidge, S.A. Science (1995) [Pubmed]
  31. Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor. Maeda, T., Takekawa, M., Saito, H. Science (1995) [Pubmed]
  32. STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction. Takeshita, T., Arita, T., Higuchi, M., Asao, H., Endo, K., Kuroda, H., Tanaka, N., Murata, K., Ishii, N., Sugamura, K. Immunity (1997) [Pubmed]
  33. Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. Kong, G.H., Bu, J.Y., Kurosaki, T., Shaw, A.S., Chan, A.C. Immunity (1995) [Pubmed]
  34. A unique set of SH3-SH3 interactions controls IB1 homodimerization. Kristensen, O., Guenat, S., Dar, I., Allaman-Pillet, N., Abderrahmani, A., Ferdaoussi, M., Roduit, R., Maurer, F., Beckmann, J.S., Kastrup, J.S., Gajhede, M., Bonny, C. EMBO J. (2006) [Pubmed]
  35. Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Joung, I., Strominger, J.L., Shin, J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
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