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Vol. 14, Issue 9, 3911-3928, September 2003

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Critical Role of Src and SHP-2 in sst2 Somatostatin Receptor-mediated Activation of SHP-1 and Inhibition of Cell Proliferation

Geraldine Ferjoux ^*, Frederic Lopez ^*, Jean-Pierre Esteve ^*, Audrey Ferrand ^*, Eric Vivier ^*, Frederic Vely , Nathalie Saint-Laurent ^*, Lucien Pradayrol ^*, Louis Buscail ^*, and Christiane Susini ^* 

^* Institut National de la Santé et de la Recherche Médicale U531, IFR31, CHU Rangueil, 31403 Toulouse, France; Centre d'Immunologie Institut National de la Santé et de la Recherche Médicale/Centre National de la Recherche Scientifique Marseille Luminy, 13288 Marseille, France

Submitted February 6, 2003; Revised April 24, 2003; Accepted April 24, 2003
Monitoring Editor: Carl-Henrik Heldin

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 G-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.

Corresponding author. E-mail address: susinich{at}toulouse.inserm.fr.

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