A Switch of G Protein-Coupled Receptor Binding Preference from Phosphoinositide 3-Kinase (PI3K)–p85 to Filamin A Negatively Controls the PI3K Pathway

Souad Najiba (1) , Nathalie Saint-Laurent (2) , Jean-Pierre Estève (3) , Stefan Schulz (4) , Elisa Boutet-Robinet (5) , Daniel Fourmy (1) , Jens Lättig (1) , Catherine Mollereau (6) , Stéphane Pyronnet (1) , Christiane Susini (2) , Corinne Bousquet (1)

1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 I2MR - Institut de médecine moléculaire de Rangueil
3 LKB (Jussieu) - Laboratoire Kastler Brossel
4 Institute of Pharmacology and Toxicology
5 ToxAlim-COMICS - Contaminants & Stress Cellulaire
6 IPBS - Institut de pharmacologie et de biologie structurale

Frequent oncogenic alterations occur in the phosphoinositide 3-kinase (PI3K) pathway, urging identification of novel negative controls. We previously reported an original mechanism for restraining PI3K activity, controlled by the somatostatin G proteincoupled receptor (GPCR) sst2 and involving a ligand-regulated interaction between sst2 with the PI3K regulatory p85 subunit. We here identify the scaffolding protein filamin A (FLNA) as a critical player regulating the dynamic of this complex. A preexisting sst2-p85 complex, which was shown to account for a significant basal PI3K activity in the absence of ligand, is disrupted upon sst2 activation. FLNA was here identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switching of GPCR binding preference from p85 toward FLNA is determined by changes in the tyrosine phosphorylation of p85- and FLNA-binding sites on sst2 upon activation. It results in the disruption of the sst2-p85 complex and the subsequent inhibition of PI3K. Knocking down FLNA expression, or abrogating FLNA recruitment to sst2, reversed the inhibition of PI3K and of tumor growth induced by sst2. Importantly, we report that this FLNA inhibitory control on PI3K can be generalized to another GPCR, the mu opioid receptor, thereby providing an unprecedented mechanism underlying GPCR-negative control on PI3K.

Domaines: Sciences du Vivant [q-bio]

Souad Najiba, Nathalie Saint-Laurent, Jean-Pierre Estève, Stefan Schulz, Elisa Boutet-Robinet, et al.. A Switch of G Protein-Coupled Receptor Binding Preference from Phosphoinositide 3-Kinase (PI3K)–p85 to Filamin A Negatively Controls the PI3K Pathway. Molecular and Cellular Biology, 2012, 32 (5), pp.1004-16. ⟨10.1128/MCB.06252-11⟩. ⟨hal-01191384⟩