ICEECE2012 Symposia Somatostatin receptors in pituitary (3 abstracts)
Somatostatin receptors and filamin: a developing story
S. Najib 1, , N. Saint-Laurent 1 , D. Fourmy 2 , S. Schulz 4 , R. Luque 5 , J. Castano 5 , M. Delisle 1, , S. Pyronnet 1, , C. Susini 1, & C. Bousquet 1,
1INSERM U1037, Toulouse cedex 4, France; 2Université Toulouse 3 Paul Sabatier, Toulouse, France; 3Toulouse Hospital, Toulouse, France; 4Jena University Hospital, Jena, Germany; 5Instituto Maimónides de Investigación Biomédica de Córdoba, Cordoba, Spain.
The G protein-coupled (GPCR) somatostatin receptor sst2 transduces the majority of somatostatin actions, including inhibition of hormone and growth factor secretion, cell survival and angiogenesis. Sst2 agonists such as octreotide are widely used for the treatment and diagnostic of human neuroendocrine tumors that frequently over-express sst2. To initiate its inhibitory signalling pathways, sst2 engages, in addition to G protein subunits, different protein partners such as phosphatases and kinases. We have reported an original mechanism for sst2 to restrain the phosphoinositide 3-kinase (PI3K) activity, involving a ligand-regulated direct interaction between sst2 with the PI3K regulatory p85 subunit. We also identified the scaffolding protein filamin-A (FLNA) as a critical player regulating the dynamic of this complex. A pre-existing 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 identified as a competitor of p85 for direct binding to two juxtaposed sites on sst2. Switch of sst2 binding preference from p85 towards FLNA is determined by changes in tyrosine phosphorylation of p85- and FLNA-binding sites on sst2 upon activation. It results in disruption of the sst2–p85 complex and subsequent inhibition of PI3K. Knocking-down FLNA expression, or abrogating FLNA recruitment to sst2, reversed inhibition of PI3K and of tumor growth induced by sst2. FLNA is an actin-binding and scaffolding protein for numerous cytosolic and transmembrane signalling proteins including GPCRs. Our results demonstrate that FLNA is critical to maintain the stability of sst2 at the membrane in close proximity with its signalling effectors including actors of the lipid PI3K family. Strikingly, in GH-secreting pituitary adenomas expressing sst2, resistance to octreotide correlates with decreased expression of FLNA, further emphasizing the critical role of FLNA in sst2 functions.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
Volume 29
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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