Indiana University-Purdue University Indianapolis (IUPUI) / Insulin-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.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/12087 |
| Date | 06 September 2016 |
| Creators | Tunduguru, Ragadeepthi |
| Contributors | Thurmond, Debbie C., Elmendorf, Jeffrey S., Atkinson, Simon J., Brozinick, Joseph T., Gunst, Susan J. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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