Résumé
OBJECTIVE-Cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic beta-cells, their precise role in the beta-cell remains unknown. Because type 2 diabetes is characterized by a deficit in beta-cell mass and increased beta-cell apoptosis, we investigated the role of CDK5 in beta-cell survival.
RESEARCH DESIGN AND METHODS-We used INS 832/13 cells, rat islets isolated from wild-type or human islet amyloid polypeptide (h-IAPP) transgenic rats, and pancreatic tissue from rats and humans with and without type 2 diabetes and investigated the effect of CDK5/p35 inhibition (by small interfering RNA or by chemical inhibition) as well as CDK5/p35 overexpression on beta-cell vulnerability to apoptosis.
RESULTS-CDK5 inhibition led to increased beta-cell apoptosis. To identify the mechanisms involved, we examined the phosphorylation state of focal adhesion kinase (Fak)(Ser732), a known target of CDK5. Following CDK5 inhibition, the phosphorylation of Fak(Ser732) decreased with resulting attenuation of phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway. Conversely, CDK5 overexpression increased Fak(Ser732) phosphorylation and protected beta-cells against apoptosis induced by the inhibition of the beta-1 integrin signaling pathway. Also, Fak(Ser732) phosphorylation was less abundant in beta-cells in both h-IAPP transgenic rats and humans with type 2 diabetes.
CONCLUSIONS-This study shows that by regulating Fak phosphorylation and subsequently PI3K/Akt survival pathway, CDK5 plays a previously unrecognized role in promoting beta-cell survival. Diabetes 60:1186-1197, 2011