Home LiteratureArticle Details
PMID: 12972574 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Critical role of Src and SHP-2 in sst2 somatostatin receptor-mediated activation of SHP-1 and inhibition of cell proliferation.

Molecular biology of the cell ·Vol. 14 ·No. 9 ·2003-09-00 ·Pages 3911-28

Ferjoux G, Lopez F, Esteve JP, Ferrand A, Vivier E, Vely F, Saint-Laurent N, Pradayrol L, Buscail L, Susini C

Abstract

The G protein-coupled sst2 somatostatin receptor acts as a negative cell growth regulator. Sst2 transmits antimitogenic signaling by recruiting and activating the tyrosine phosphatase SHP-1. We now identified Src and SHP-2 as sst2-associated molecules and demonstrated their role in sst2 signaling. Surface plasmon resonance and mutation analyses revealed that SHP-2 directly associated with phosphorylated tyrosine 228 and 312, which are located in sst2 ITIMs (immunoreceptor tyrosine-based inhibitory motifs). This interaction was required for somatostatin-induced SHP-1 recruitment and activation and consequent inhibition of cell proliferation. Src interacted with sst2 and somatostatin promoted a transient Gbetagamma-dependent Src activation concomitant with sst2 tyrosine hyperphosphorylation and SHP-2 activation. These steps were abrogated with catalytically inactive Src. Both catalytically inactive Src and SHP-2 mutants abolished somatostatin-induced SHP-1 activation and cell growth inhibition. Sst2-Src-SHP-2 complex formation was dynamic. Somatostatin further induced sst2 tyrosine dephosphorylation and complex dissociation accompanied by Src and SHP-2 inhibition. These steps were defective in cells expressing a catalytically inactive Src mutant. All these data suggest that Src acts upstream of SHP-2 in sst2 signaling and provide evidence for a functional role for Src and SHP-2 downstream of an inhibitory G protein-coupled receptor.

MeSH Terms
Amino Acid Motifs/physiology Animals Antineoplastic Combined Chemotherapy Protocols COS Cells Cell Division/physiology Chlorocebus aethiops Cricetinae Cyclophosphamide DNA Mutational Analysis Doxorubicin Intracellular Signaling Peptides and Proteins Models, Molecular Phosphorylation Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases/metabolism Rats Receptors, Somatostatin/analysis,metabolism Somatostatin/analogs & derivatives,pharmacology Surface Plasmon Resonance Vincristine src-Family Kinases/metabolism
Chemicals
Intracellular Signaling Peptides and Proteins Receptors, Somatostatin vapreotide Somatostatin Vincristine Doxorubicin Cyclophosphamide somatostatin receptor 2 src-Family Kinases Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases Ptpn11 protein, rat Ptpn6 protein, rat
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Ferjoux Geraldine
Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France.
Lopez Frederic
Esteve Jean-Pierre
Ferrand Audrey
Vivier Eric
Vely Frederic
Saint-Laurent Nathalie
Pradayrol Lucien
Buscail Louis
Susini Christiane
Supplementary Concepts
CAV protocol (Protocol)
References (68)
68 references, click to expand
  1. 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
  2. Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling.
    J Biol Chem. 1994 Feb 25;269(8):6193-7 PMID: 8119963
  3. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2.
    Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2315-9 PMID: 7907795
  4. Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains.
    J Biol Chem. 1995 Feb 17;270(7):2897-900 PMID: 7531695
  5. Fyn kinase-directed activation of SH2 domain-containing protein-tyrosine phosphatase SHP-2 by Gi protein-coupled receptors in Madin-Darby canine kidney cells.
    J Biol Chem. 1999 Apr 30;274(18):12401-7 PMID: 10212213
  6. sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1). Evidence for the role of SHP-1.
    J Biol Chem. 1999 May 21;274(21):15186-93 PMID: 10329727
  7. Regulation of immune responses through inhibitory receptors.
    Annu Rev Immunol. 1999;17:875-904 PMID: 10358776
  8. Agonist-dependent interaction of the rat somatostatin receptor subtype 2 with cortactin-binding protein 1.
    J Biol Chem. 1999 Jun 25;274(26):18153-6 PMID: 10373412
  9. Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1.
    Mol Cell Biol. 2001 Jun;21(11):3671-83 PMID: 11340161
  10. Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2.
    J Biol Chem. 2001 Jun 29;276(26):24380-7 PMID: 11323411
  11. The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells.
    Mol Endocrinol. 1994 Oct;8(10):1289-97 PMID: 7854346
  12. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1580-4 PMID: 7878022
  13. Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB1.
    Science. 1995 Apr 14;268(5208):293-7 PMID: 7716523
  14. The phosphotyrosine phosphatase PTP1D, but not PTP1C, is an essential mediator of fibroblast proliferation induced by tyrosine kinase and G protein-coupled receptors.
    J Biol Chem. 1995 May 5;270(18):11017-24 PMID: 7537742
  15. Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine phosphatases.
    J Immunol. 1996 Jun 15;156(12):4531-4 PMID: 8648092
  16. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation.
    Nature. 1996 Oct 10;383(6600):547-50 PMID: 8849729
  17. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion.
    Mol Cell Biol. 1996 Dec;16(12):6887-99 PMID: 8943344
  18. Protein tyrosine phosphatases in signal transduction.
    Curr Opin Cell Biol. 1997 Apr;9(2):193-204 PMID: 9069265
  19. Coupling specificity between somatostatin receptor sst2A and G proteins: isolation of the receptor-G protein complex with a receptor antibody.
    Mol Endocrinol. 1997 May;11(5):527-37 PMID: 9139797
  20. Activation in vitro of somatostatin receptor subtypes 2, 3, or 4 stimulates protein tyrosine phosphatase activity in membranes from transfected Ras-transformed NIH 3T3 cells: coexpression with catalytically inactive SHP-2 blocks responsiveness.
    Mol Endocrinol. 1997 Jul;11(8):1062-9 PMID: 9212054
  21. Differential association of phosphatases with hematopoietic co-receptors bearing immunoreceptor tyrosine-based inhibition motifs.
    Eur J Immunol. 1997 Aug;27(8):1994-2000 PMID: 9295037
  22. The tyrosine phosphatase SHP-1 associates with the sst2 somatostatin receptor and is an essential component of sst2-mediated inhibitory growth signaling.
    J Biol Chem. 1997 Sep 26;272(39):24448-54 PMID: 9305905
  23. Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases.
    Eur J Immunol. 1998 Jan;28(1):264-76 PMID: 9485206
  24. Crystal structure of the tyrosine phosphatase SHP-2.
    Cell. 1998 Feb 20;92(4):441-50 PMID: 9491886
  25. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1.
    Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2446-51 PMID: 9482905
  26. sst2 somatostatin receptor mediates negative regulation of insulin receptor signaling through the tyrosine phosphatase SHP-1.
    J Biol Chem. 1998 Mar 20;273(12):7099-106 PMID: 9507021
  27. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2.
    Structure. 1998 Mar 15;6(3):249-54 PMID: 9551546
  28. The elucidation of somatostatin receptor functions: a current view.
    Rev Physiol Biochem Pharmacol. 1998;133:55-108 PMID: 9600011
  29. G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization.
    J Biol Chem. 1998 Jul 24;273(30):18677-80 PMID: 9668034
  30. SHP-2, SH2-containing protein tyrosine phosphatase-2.
    Int J Biochem Cell Biol. 1998 May;30(5):559-66 PMID: 9693956
  31. The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling.
    J Biol Chem. 1998 Oct 9;273(41):26908-14 PMID: 9756938
  32. Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates.
    J Biol Chem. 1998 Oct 23;273(43):28332-40 PMID: 9774457
  33. Regulation of angiotensin II-induced JAK2 tyrosine phosphorylation: roles of SHP-1 and SHP-2.
    Am J Physiol. 1998 Nov;275(5 Pt 1):C1216-23 PMID: 9814969
  34. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells.
    J Biol Chem. 1999 Jan 1;274(1):335-44 PMID: 9867848
  35. Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1).
    Mol Endocrinol. 1999 Jan;13(1):24-37 PMID: 9892010
  36. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
    Science. 1999 Jan 29;283(5402):655-61 PMID: 9924018
  37. Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2.
    Mol Cell Biol. 1999 Apr;19(4):3205-15 PMID: 10082587
  38. Molecular tinkering of G protein-coupled receptors: an evolutionary success.
    EMBO J. 1999 Apr 1;18(7):1723-9 PMID: 10202136
  39. The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism.
    Oncogene. 1999 Mar 18;18(11):1911-20 PMID: 10208413
  40. Regulation of tyrosine kinase cascades by G-protein-coupled receptors.
    Curr Opin Cell Biol. 1999 Apr;11(2):177-83 PMID: 10209148
  41. Neuronal nitric oxide synthase: a substrate for SHP-1 involved in sst2 somatostatin receptor growth inhibitory signaling.
    FASEB J. 2001 Oct;15(12):2300-2 PMID: 11511520
  42. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine.
    Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71 PMID: 11698646
  43. Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils.
    Nat Med. 2002 Jan;8(1):61-7 PMID: 11786908
  44. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
    J Cell Sci. 2002 Feb 1;115(Pt 3):455-65 PMID: 11861753
  45. Cell surface glycoprotein PZR is a major mediator of concanavalin A-induced cell signaling.
    J Biol Chem. 2002 Mar 8;277(10):7882-8 PMID: 11751924
  46. Beta-arrestin is involved in the desensitization but not in the internalization of the somatostatin receptor 2A expressed in CHO cells.
    FEBS Lett. 2002 Apr 10;516(1-3):124-8 PMID: 11959117
  47. Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2.
    Mol Cell Biol. 2002 Jun;22(12):4062-72 PMID: 12024020
  48. Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase alpha.
    EMBO J. 2002 Jun 17;21(12):2977-89 PMID: 12065411
  49. Selective regulation of endogenous G protein-coupled receptors by arrestins in HEK293 cells.
    J Biol Chem. 2000 Apr 28;275(17):12900-8 PMID: 10777589
  50. Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction.
    Curr Opin Immunol. 2000 Jun;12(3):307-15 PMID: 10781410
  51. Identification and characterization of leukocyte-associated Ig-like receptor-1 as a major anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells.
    J Biol Chem. 2000 Jun 9;275(23):17440-6 PMID: 10764762
  52. Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9180-5 PMID: 10900262
  53. Src tyrosine kinase is a novel direct effector of G proteins.
    Cell. 2000 Sep 1;102(5):635-46 PMID: 11007482
  54. Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation.
    J Biol Chem. 2000 Dec 8;275(49):38131-4 PMID: 11013230
  55. beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors.
    J Biol Chem. 2000 Dec 8;275(49):38659-66 PMID: 10995758
  56. Recruitment of the protein-tyrosine phosphatase SHP-2 to the C-terminal tyrosine of the prolactin receptor and to the adaptor protein Gab2.
    J Biol Chem. 2000 Dec 15;275(50):39073-80 PMID: 10991949
  57. Selected glimpses into the activation and function of Src kinase.
    Oncogene. 2000 Nov 20;19(49):5620-35 PMID: 11114743
  58. Combinatorial control of the specificity of protein tyrosine phosphatases.
    Curr Opin Cell Biol. 2001 Apr;13(2):182-95 PMID: 11248552
  59. Inhibition of antigen-receptor signaling by Platelet Endothelial Cell Adhesion Molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56(lck).
    Blood. 2001 Apr 15;97(8):2351-7 PMID: 11290597
  60. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain.
    J Biol Chem. 1999 Nov 12;274(46):32997-3001 PMID: 10551867
  61. Early signaling via inhibitory and activating NK receptors.
    Hum Immunol. 2000 Jan;61(1):51-64 PMID: 10658978
  62. New roles for Src kinases in control of cell survival and angiogenesis.
    Cell. 2000 Feb 4;100(3):293-6 PMID: 10676810
  63. Dissecting the interaction of SHP-2 with PZR, an immunoglobulin family protein containing immunoreceptor tyrosine-based inhibitory motifs.
    J Biol Chem. 2000 Feb 25;275(8):5453-9 PMID: 10681522
  64. Regulation of calcium-sensitive tyrosine kinase Pyk2 by angiotensin II in endothelial cells. Roles of Yes tyrosine kinase and tyrosine phosphatase SHP-2.
    J Biol Chem. 2000 Mar 24;275(12):8389-96 PMID: 10722671
  65. Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells.
    J Exp Med. 2002 Sep 2;196(5):667-78 PMID: 12208881
  66. A novel protein-protein interaction between a G protein-coupled receptor and the phosphatase SHP-2 is involved in bradykinin-induced inhibition of cell proliferation.
    J Biol Chem. 2002 Oct 25;277(43):40375-83 PMID: 12177051
  67. Ligand: a versatile computerized approach for characterization of ligand-binding systems.
    Anal Biochem. 1980 Sep 1;107(1):220-39 PMID: 6254391
  68. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney.
    Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):251-5 PMID: 1346068
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e03-02-0069
Published
2003-09-00
Epub
2003-00-11
Pages
3911-28
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC196590
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e03-02-0069 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2