title: In vivo role of focal adhesion kinase in regulating pancreatic β-cell mass and function through insulin signaling, actin dynamics, and granule trafficking.
abstract: 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(+)fak(fl/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 Ca(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 β-cell viability and function through regulation in insulin signaling, actin dynamics, and granule trafficking.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.forename: Marina
authors.initials: M
authors.lastname: Casimir
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.forename: Diana
authors.initials: D
authors.lastname: Choi
authors.forename: Xiao Qing
authors.initials: XQ
authors.lastname: Dai
authors.forename: Catherine
authors.initials: C
authors.lastname: Hajmrle
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Spigelman
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis; D002470:Cell Survival; D005089:Exocytosis; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D051419:Paxillin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D016608:Talin / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D007328:Insulin; D051419:Paxillin; D016608:Talin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002118:Calcium