title: Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo.
abstract: The p21-activated kinase PAK1 is implicated in tumorigenesis, and efforts to inhibit PAK1 signaling as a means to induce tumor cell apoptosis are underway. However, PAK1 has also been implicated as a positive effector of mechanisms in clonal pancreatic beta cells and skeletal myotubes that would be crucial to maintaining glucose homeostasis in vivo. Of relevance, human islets of Type 2 diabetic donors contained ~80% less PAK1 protein compared with non-diabetics, implicating PAK1 in islet signaling/scaffolding functions. Mimicking this, islets from PAK1(-/-) knock-out mice exhibited profound defects in the second/sustained-phase of insulin secretion. Reiteration of this specific defect by human islets treated with the PAK1 signaling inhibitor IPA3 revealed PAK1 signaling to be of primary functional importance. Analyses of human and mouse islet beta cell signaling revealed PAK1 activation to be 1) dependent upon Cdc42 abundance, 2) crucial for signaling downstream to activate ERK1/2, but 3) dispensable for cofilin phosphorylation. Importantly, the PAK1(-/-) knock-out mice were found to exhibit whole body glucose intolerance in vivo. Exacerbating this, the PAK1(-/-) knock-out mice also exhibited peripheral insulin resistance. Insulin resistance was coupled to ablation of insulin-stimulated GLUT4 translocation in skeletal muscle from PAK1(-/-) knock-out mice, and in sharp contrast to islet beta cells, skeletal muscle PAK1 loss was underscored by defective cofilin phosphorylation but normal ERK1/2 activation. Taken together, these data provide the first human islet and mammalian in vivo data unveiling the key and crucial roles for differential PAK1 signaling in the multi-tissue regulation of whole body glucose homeostasis.
authors.affiliation: Basic Diabetes Group, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202.
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Basic Diabetes Group, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Oh
authors.affiliation: Basic Diabetes Group, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: Basic Diabetes Group, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202. Electronic address: dthurmon@iupui.edu.
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Thurmond
mesh_terms: D000818:Animals; D016466:CHO Cells; D051338:Cofilin 1; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051338:Cofilin 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020764:cdc42 GTP-Binding Protein; D005947:Glucose