Nexilin, a Cardiomyopathy-Associated F-Actin Binding Protein, Binds and Regulates IRS1 Signaling in Skeletal Muscle Cells

Andrew Lee, Fumihiko Hakuno, Paul Northcott, Jeffrey E. Pessin, Maria Rozakis Adcock

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Insulin stimulates glucose uptake through a highly organized and complex process that involves movement of the glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane. Previous studies in L6 skeletal muscle cells have shown that insulin-induced activation and assembly of insulin receptor substrate 1 (IRS1) and p85α the regulatory subunit of the Type 1A phosphatidylinositol-3-kinase (PI3K), within remodeled actin-rich membrane structures is critical for downstream signalling mediating the translocation of GLUT4. The mechanism for localization within actin cytoskeletal scaffolds is not known, as direct interaction of IRS1 or p85α with F-actin has not been demonstrated. Here we show that nexilin, a F-actin binding protein implicated in the pathogenesis of familial dilated cardiomyopathies, preferentially binds to IRS1 over IRS2 to influence glucose transport in skeletal muscle cells. Nexilin stably associates with IRS1 under basal conditions in L6 myotubes and this complex is disassembled by insulin. Exposure of L6 myotubes to Latrunculin B disrupts the spatial patterning of nexilin and its transient association with IRS1. Functional silencing of nexilin has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, however it enhances recruitment of p85α to IRS1 resulting in increased PI-3, 4, 5-P3 formation, coincident with enhanced AKT activation and glucose uptake. By contrast, overexpression of nexilin inhibits transmission of IRS1 signals to AKT. Based on these findings we propose that nexilin may tether IRS1 to actin-rich structures under basal conditions, confining IRS1 signaling to specific subcellular locations in the cell. Insulin-elicited release of this constraint may enhance the efficiency of IRS1/PI3K interaction and PI-3, 4, 5-P3 production at localized sites. Moreover, the selective binding of nexilin to IRS1 and not IRS2 may contribute to the differential specificity of IRS isoforms in the modulation of GLUT4 trafficking in skeletal muscle cells.

Original languageEnglish (US)
Article numbere55634
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 30 2013

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microfilament proteins
Insulin Receptor Substrate Proteins
cardiomyopathy
Cardiomyopathies
myocytes
Muscle Cells
actin
Muscle
skeletal muscle
Skeletal Muscle
Cells
insulin
glucose transporters
Facilitative Glucose Transport Proteins
Insulin
Actins
Phosphatidylinositol 3-Kinase
Skeletal Muscle Fibers
phosphatidylinositol 3-kinase
Glucose

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nexilin, a Cardiomyopathy-Associated F-Actin Binding Protein, Binds and Regulates IRS1 Signaling in Skeletal Muscle Cells. / Lee, Andrew; Hakuno, Fumihiko; Northcott, Paul; Pessin, Jeffrey E.; Adcock, Maria Rozakis.

In: PLoS One, Vol. 8, No. 1, e55634, 30.01.2013.

Research output: Contribution to journalArticle

Lee, Andrew ; Hakuno, Fumihiko ; Northcott, Paul ; Pessin, Jeffrey E. ; Adcock, Maria Rozakis. / Nexilin, a Cardiomyopathy-Associated F-Actin Binding Protein, Binds and Regulates IRS1 Signaling in Skeletal Muscle Cells. In: PLoS One. 2013 ; Vol. 8, No. 1.
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