In vivo role of focal adhesion kinase in regulating pancreatic [beta]-cell mass and function through insulin signaling, actin dynamics, and granule trafficking

Focal adhesion kinase (FAK) acts as an adaptor at the focal contacts serving as a junction between the extracellular matrix and actin cytoskeleton. Actin dynamics is known as a determinant step in insulin secretion. Additionally, FAK has been shown to regulate insulin signaling. To investigate the essential physiological role of FAK in pancreatic [beta]-cells in vivo, we generated a transgenic mouse model using rat insulin promoter (RIP)-driven Cre-loxP recombination system to specifically delete FAK in pancreatic [beta]-cells. These [RIPcre.sup.+][fak.sup.fl/fl] mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced [beta]-cell viability and proliferation resulting in decreased [beta]-cell mass was observed in these mice, which was associated with attenuated insulin/Akt (also known as protein kinase B) and extracellular signal-related kinase 1/2 signaling and increased caspase 3 activation. FAK-deficient [beta]-cells exhibited impaired insulin secretion with normal glucose sensing and preserved [Ca.sup.2+] influx in response to glucose, but a reduced number of docked insulin granules and insulin exocytosis were found, which was associated with a decrease in focal proteins, paxillin and talin, and an impairment in actin depolymerization. This study is the first to show in vivo that FAK is critical for pancreatic [beta]-cell viability and function through regulation in insulin signaling, actin dynamics, and granule trafficking. Diabetes 61:1708-1718, 2012