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PMID: 7511210 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav.

Molecular and cellular biology ·Vol. 14 ·No. 4 ·1994-04-00 ·Pages 2777-85

Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, Barbacid M, Sabe H, Hanafusa H, Yi T

Abstract

Src homology 2 (SH2) domains provide specificity to intracellular signaling by binding to specific phosphotyrosine (phospho-Tyr)-containing sequences. We recently developed a technique using a degenerate phosphopeptide library to predict the specificity of individual SH2 domains (src family members, Abl, Nck, Sem5, phospholipase C-gamma, p85 subunit of phosphatidylinositol-3-kinase, and SHPTP2 (Z. Songyang, S. E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W. G. Haser, F. King, T. Roberts, S. Ratnofsky, R. J. Lechleider, B. G. Neel, R. B. Birge, J. E. Fajardo, M. M. Chou, H. Hanafusa, B. Schaffhausen, and L. C. Cantley, Cell 72:767-778, 1993). We report here the optimal recognition motifs for SH2 domains from GRB-2, Drk, Csk, Vav, fps/fes, SHC, Syk (carboxy-terminal SH2), 3BP2, and HCP (amino-terminal SH2 domain, also called PTP1C and SHPTP1). As predicted, SH2 domains from proteins that fall into group I on the basis of a Phe or Tyr at the beta D5 position (GRB-2, 3BP2, Csk, fps/fes, Syk C-terminal SH2) select phosphopeptides with the general motif phospho-Tyr-hydrophilic (residue)-hydrophilic (residue)-hydrophobic (residue). The SH2 domains of SHC and HCP (group III proteins with Ile, Leu, of Cys at the beta D5 position) selected the general motif phospho-Tyr-hydrophobic-Xxx-hydrophobic, also as predicted. Vav, which has a Thr at the beta D5 position, selected phospho-Tyr-Met-Glu-Pro as the optimal motif. Each SH2 domain selected a unique optimal motif distinct from motifs previously determined for other SH2 domains. These motifs are used to predict potential sites in signaling proteins for interaction with specific SH2 domain-containing proteins. The Syk SH2 domain is predicted to bind to Tyr-hydrophilic-hydrophilic-Leu/Ile motifs like those repeated at 10-residue intervals in T- and B-cell receptor-associated proteins. SHC is predicted to bind to a subgroup og these same motifs. A structural basis for the association of Csk with Src family members is also suggested from these studies.

MeSH Terms
Amino Acid Sequence Animals Binding Sites Drosophila melanogaster/metabolism Genes, src Mice Molecular Sequence Data Phosphatidylinositol 3-Kinases Phosphopeptides/chemical synthesis Phosphotransferases (Alcohol Group Acceptor)/metabolism Phosphotyrosine Proteins/chemistry,metabolism Receptors, Antigen, B-Cell/metabolism Receptors, Antigen, T-Cell/metabolism Recombinant Fusion Proteins/isolation & purification,metabolism Sequence Homology, Amino Acid Signal Transduction Substrate Specificity Tyrosine/analogs & derivatives,metabolism
Chemicals
Phosphopeptides Proteins Receptors, Antigen, B-Cell Receptors, Antigen, T-Cell Recombinant Fusion Proteins Phosphotyrosine Tyrosine Phosphatidylinositol 3-Kinases Phosphotransferases (Alcohol Group Acceptor)
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Songyang Z
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
Shoelson S E
McGlade J
Olivier P
Pawson T
Bustelo X R
Barbacid M
Sabe H
Hanafusa H
Yi T
References (49)
49 references, click to expand
  1. Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors.
    Science. 1990 Nov 16;250(4983):979-82 PMID: 2173144
  2. Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis.
    J Biol Chem. 1991 Aug 25;266(24):15790-6 PMID: 1874735
  3. Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand.
    Mol Cell Biol. 1993 Jun;13(6):3350-8 PMID: 7684496
  4. Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation.
    Science. 1993 May 7;260(5109):822-5 PMID: 8484124
  5. Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms.
    Cell. 1993 Mar 12;72(5):779-90 PMID: 7680960
  6. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck.
    Nature. 1993 Mar 4;362(6415):87-91 PMID: 7680435
  7. The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp.
    Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6939-43 PMID: 7688466
  8. Oncogenes and signal transduction.
    Cell. 1991 Jan 25;64(2):281-302 PMID: 1846320
  9. Identification of two C-terminal autophosphorylation sites in the PDGF beta-receptor: involvement in the interaction with phospholipase C-gamma.
    EMBO J. 1992 Nov;11(11):3911-9 PMID: 1396585
  10. vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells.
    EMBO J. 1989 Aug;8(8):2283-90 PMID: 2477241
  11. Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal.
    Cell. 1993 Apr 23;73(2):321-34 PMID: 7682895
  12. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein.
    Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9166-70 PMID: 1717999
  13. Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins.
    Cell. 1989 Sep 22;58(6):1121-33 PMID: 2550144
  14. Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions.
    EMBO J. 1992 Apr;11(4):1365-72 PMID: 1314163
  15. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation.
    Nature. 1985 May 16-22;315(6016):239-42 PMID: 2987699
  16. Association between the PDGF receptor and members of the src family of tyrosine kinases.
    Cell. 1990 Aug 10;62(3):481-92 PMID: 1696179
  17. PDGF beta-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex.
    Cell. 1990 Apr 6;61(1):125-33 PMID: 2156626
  18. Interkinase domain of kit contains the binding site for phosphatidylinositol 3' kinase.
    Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):678-82 PMID: 1370584
  19. Molecular cloning and expression of chicken C-terminal Src kinase: lack of stable association with c-Src protein.
    Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2190-4 PMID: 1372437
  20. A completely transformation-defective point mutant of polyomavirus middle T antigen which retains full associated phosphatidylinositol kinase activity.
    J Virol. 1990 Sep;64(9):4454-61 PMID: 2166824
  21. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.
    J Biol Chem. 1990 Feb 25;265(6):3116-23 PMID: 1968060
  22. Molecular cloning and characterization of the human dbl proto-oncogene: evidence that its overexpression is sufficient to transform NIH/3T3 cells.
    EMBO J. 1988 Aug;7(8):2465-73 PMID: 3056717
  23. A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos.
    Cell. 1993 Apr 9;73(1):179-91 PMID: 8462098
  24. Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro.
    Cell. 1989 Jun 30;57(7):1109-22 PMID: 2472219
  25. SH2 domains recognize specific phosphopeptide sequences.
    Cell. 1993 Mar 12;72(5):767-78 PMID: 7680959
  26. Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity.
    Cell. 1987 Sep 25;50(7):1021-9 PMID: 2441878
  27. A protein tyrosine kinase involved in regulation of pp60c-src function.
    J Biol Chem. 1989 Dec 15;264(35):20886-93 PMID: 2480346
  28. Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways.
    Cell. 1992 May 1;69(3):413-23 PMID: 1374684
  29. The NPXY internalization signal of the LDL receptor adopts a reverse-turn conformation.
    Cell. 1991 Dec 20;67(6):1195-201 PMID: 1760844
  30. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate.
    Nature. 1988 Apr 14;332(6165):644-6 PMID: 2833705
  31. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor.
    J Biol Chem. 1993 Oct 15;268(29):21478-81 PMID: 7691811
  32. Human cellular fps/fes cDNA rescued via retroviral shuttle vector encodes myeloid cell NCP92 and has transforming potential.
    Oncogene Res. 1987 Sep-Oct;1(4):441-58 PMID: 3329718
  33. Interaction of Shc with the zeta chain of the T cell receptor upon T cell activation.
    Science. 1993 Nov 5;262(5135):902-5 PMID: 8235613
  34. A phosphatidylinositol-3 kinase binds to platelet-derived growth factor receptors through a specific receptor sequence containing phosphotyrosine.
    Mol Cell Biol. 1991 Feb;11(2):1125-32 PMID: 1703628
  35. SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors.
    Mol Cell Biol. 1992 Mar;12(3):991-7 PMID: 1372092
  36. Evidence for autoinhibitory regulation of the c-src gene product. A possible interaction between the src homology 2 domain and autophosphorylation site.
    J Biol Chem. 1993 Jan 15;268(2):1132-40 PMID: 7678249
  37. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling.
    EMBO J. 1993 May;12(5):1929-36 PMID: 8491186
  38. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.
    Mol Cell Biol. 1993 Nov;13(11):6889-96 PMID: 7692233
  39. Identification of a ten-amino acid proline-rich SH3 binding site.
    Science. 1993 Feb 19;259(5098):1157-61 PMID: 8438166
  40. SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C gamma.
    EMBO J. 1992 Feb;11(2):559-67 PMID: 1537335
  41. SH2 and SH3 domains.
    Curr Biol. 1993 Jul 1;3(7):434-42 PMID: 15335710
  42. Antigen receptor tail clue.
    Nature. 1989 Mar 30;338(6214):383-4 PMID: 2927501
  43. Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit.
    J Biol Chem. 1993 May 5;268(13):9478-83 PMID: 7683653
  44. Transformation-defective mutants of polyomavirus middle T antigen associate with phosphatidylinositol 3-kinase (PI 3-kinase) but are unable to maintain wild-type levels of PI 3-kinase products in intact cells.
    J Virol. 1992 Mar;66(3):1702-8 PMID: 1371171
  45. CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase.
    Science. 1993 May 14;260(5110):986-9 PMID: 7684160
  46. A putative modular domain present in diverse signaling proteins.
    Cell. 1993 May 21;73(4):629-30 PMID: 8500161
  47. Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates.
    Nature. 1992 Mar 5;356(6364):68-71 PMID: 1311423
  48. Identification of Trk binding sites for SHC and phosphatidylinositol 3'-kinase and formation of a multimeric signaling complex.
    J Biol Chem. 1993 Nov 5;268(31):22963-6 PMID: 8226808
  49. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.
    Cell. 1992 Jul 10;70(1):93-104 PMID: 1623525
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.14.4.2777-2785.1994
Published
1994-04-00
Pages
2777-85
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC358643
Subset
IM
External Links
PubMed source DOI: 10.1128/mcb.14.4.2777-2785.1994 PMC Full Text View journal details
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