Critical Role of Src and SHP-2 in sst2 Somatostatin Receptor-mediated Activation of SHP-1 and Inhibition of Cell Proliferation
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- Geraldine Ferjoux
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Frederic Lopez
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Jean-Pierre Esteve
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Audrey Ferrand
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Eric Vivier
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Frederic Vely
- Centre d'Immunologie Institut National de la Santé et de la Recherche Médicale/Centre National de la Recherche Scientifique Marseille Luminy, 13288 Marseille, France
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- Nathalie Saint-Laurent
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Lucien Pradayrol
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Louis Buscail
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
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- Christiane Susini
- Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France
抄録
<jats:p>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 Gβγ-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.</jats:p>
収録刊行物
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- Molecular Biology of the Cell
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Molecular Biology of the Cell 14 (9), 3911-3928, 2003-09
American Society for Cell Biology (ASCB)