In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic β-Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking
- Erica P. Cai1,2,
- Marina Casimir3,
- Stephanie A. Schroer2,
- Cynthia T. Luk1,2,
- Sally Yu Shi1,2,
- Diana Choi1,
- Xiao Qing Dai3,
- Catherine Hajmrle3,
- Aliya F. Spigelman3,
- Dan Zhu4,5,
- Herbert Y. Gaisano1,4,5,
- Patrick E. MacDonald3⇓ and
- Minna Woo1,2,4,6⇓
- 1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- 2Toronto General Research Institute, Toronto, Ontario, Canada
- 3Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- 4Department of Medicine, University of Toronto, Ontario, Canada
- 5Department of Physiology, University of Toronto, Ontario, Canada
- 6Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Corresponding author: Minna Woo, , or Patrick MacDonald, .
E.P.C. and M.C. contributed equally to this study.
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 β-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 β-cells. These RIPcre+fakfl/fl mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell viability and proliferation resulting in decreased β-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 β-cells exhibited impaired insulin secretion with normal glucose sensing and preserved Ca2+ 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 β-cell viability and function through regulation in insulin signaling, actin dynamics, and granule trafficking.
- Received September 25, 2011.
- Accepted February 24, 2012.
- © 2012 by the American Diabetes Association.
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