RGD Reference Report - Signaling of the p21-activated kinase (PAK1) coordinates insulin-stimulated actin remodeling and glucose uptake in skeletal muscle cells. - Rat Genome Database

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Signaling of the p21-activated kinase (PAK1) coordinates insulin-stimulated actin remodeling and glucose uptake in skeletal muscle cells.

Authors: Tunduguru, R  Chiu, TT  Ramalingam, L  Elmendorf, JS  Klip, A  Thurmond, DC 
Citation: Tunduguru R, etal., Biochem Pharmacol. 2014 Nov 15;92(2):380-8. doi: 10.1016/j.bcp.2014.08.033. Epub 2014 Sep 6.
RGD ID: 11533947
Pubmed: PMID:25199455   (View Abstract at PubMed)
PMCID: PMC4418524   (View Article at PubMed Central)
DOI: DOI:10.1016/j.bcp.2014.08.033   (Journal Full-text)

Skeletal muscle accounts for approximately 80% of postprandial glucose clearance, and skeletal muscle glucose clearance is crucial for maintaining insulin sensitivity and euglycemia. Insulin-stimulated glucose clearance/uptake entails recruitment of glucose transporter 4 (GLUT4) to the plasma membrane (PM) in a process that requires cortical F-actin remodeling; this process is dysregulated in Type 2 Diabetes. Recent studies have implicated PAK1 as a required element in GLUT4 recruitment in mouse skeletal muscle in vivo, although its underlying mechanism of action and requirement in glucose uptake remains undetermined. Toward this, we have employed the PAK1 inhibitor, IPA3, in studies using L6-GLUT4-myc muscle cells. IPA3 fully ablated insulin-stimulated GLUT4 translocation to the PM, corroborating the observation of ablated insulin-stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1(-/-) knockout mice. IPA3-treatment also abolished insulin-stimulated glucose uptake into skeletal myotubes. Mechanistically, live-cell imaging of myoblasts expressing the F-actin biosensor LifeAct-GFP treated with IPA3 showed blunting of the normal insulin-induced cortical actin remodeling. This blunting was underpinned by a loss of normal insulin-stimulated cofilin dephosphorylation in IPA3-treated myoblasts. These findings expand upon the existing model of actin remodeling in glucose uptake, by placing insulin-stimulated PAK1 signaling as a required upstream step to facilitate actin remodeling and subsequent cofilin dephosphorylation. Active, dephosphorylated cofilin then provides the G-actin substrate for continued F-actin remodeling to facilitate GLUT4 vesicle translocation for glucose uptake into the skeletal muscle cell.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of insulin receptor signaling pathway  IMP 11533947 RGD 
positive regulation of protein targeting to membrane  IMP 11533947 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pak1  (p21 (RAC1) activated kinase 1)


Additional Information