Regulation of skeletal muscle insulin sensitivity by PAK1

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dc.contributor.advisorThurmond, Debbie C.
dc.contributor.advisorElmendorf, Jeffrey S.
dc.contributor.authorTunduguru, Ragadeepthi
dc.contributor.otherAtkinson, Simon J.
dc.contributor.otherBrozinick, Joseph T.
dc.contributor.otherGunst, Susan J.
dc.date.accessioned2017-03-20T19:28:04Z
dc.date.available2018-01-02T10:30:11Z
dc.date.issued2016-09-06
dc.degree.date2016en_US
dc.degree.disciplineDepartment of Biochemistry & Molecular Biology
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractInsulin-stimulated glucose uptake into skeletal muscle cells requires translocation of the glucose transporter-4 (GLUT4) from the cell interior to the plasma membrane. Insulin-stimulated GLUT4 vesicle translocation is dysregulated in Type 2 diabetes (T2D). The Group I p21–activated kinase (PAK1) is a required element in insulin-stimulated GLUT4 vesicle translocation in mouse skeletal muscle in vivo, although its placement and function(s) in the canonical insulin signaling cascade in skeletal muscle cells, remain undetermined. Therefore, the objective of my project is to determine the molecular mechanism(s) underlying the requirement for PAK1 in the process of insulin-stimulated GLUT4 vesicle translocation and subsequent glucose uptake by skeletal muscle cells. Toward this, my studies demonstrate that the pharmacological inhibition of PAK1 activation blunts insulin-stimulated GLUT4 translocation and subsequent glucose uptake into L6-GLUT4myc skeletal myotubes. Inhibition of PAK1 activation also ablates insulin-stimulated F-actin cytoskeletal remodeling, a process known to be required for mobilizing GLUT4 vesicles to the plasma membrane. Consistent with this mechanism, PAK1 activation was also required for the activation of cofilin, another protein implicated in F-actin remodeling. Interestingly, my studies reveal a novel molecular mechanism involving PAK1 signaling to p41-ARC, a regulatory subunit of the cytoskeletal Arp2/3 complex, and its interactions with another cytoskeletal factor, N-WASP, to elicit the insulin-stimulated F-actin remodeling in skeletal muscle cells. Pharmacological inactivation of N-WASP fully abrogated insulin-stimulated GLUT4 vesicle translocation to the cell surface, coordinate with blunted F-actin remodeling. Furthermore, my studies revealed new insulin-induced interactions amongst N WASP, actin, p41-ARC and PAK1; inactivation of PAK1 signaling blocked these dynamic interactions. Taken together, the above studies demonstrate the significance of PAK1 and its downstream signaling to F-actin remodeling in insulin-stimulated GLUT4 vesicle translocation and glucose uptake, revealing new signaling elements that may prove to be promising targets for future therapeutic design.en_US
dc.identifier.doi10.7912/C2FS4X
dc.identifier.urihttps://hdl.handle.net/1805/12087
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1807
dc.language.isoen_USen_US
dc.subjectActin remodelingen_US
dc.subjectGLUT4en_US
dc.subjectInsulin sensitivityen_US
dc.subjectPAK1en_US
dc.subjectSkeletal muscleen_US
dc.subjectGlucose uptakeen_US
dc.titleRegulation of skeletal muscle insulin sensitivity by PAK1en_US
dc.typeDissertation
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