APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor.
Bottom Line: However, the mechanism of IRS1/2 recruitment to the IR remains elusive.Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction.The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR.
Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.Show MeSH
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Mentions: APPL1 contains several potential phosphorylation sites including Ser151, Ser401, Ser427, and Ser430 (Gant-Branum et al., 2010) that may be subjected to insulin- or adiponectin-stimulated phosphorylation. Among these potential phosphorylation sites, Ser401 is highly conserved in APPL1 among different species, and this residue is absent in the corresponding location of its isoform APPL2 (Figure S4A); the latter does not interact with the IR (data not shown). To determine the potential roles of APPL1 phosphorylation, we generated a phosphospecific antibody to Ser401 of APPL1 (Figure S4B). By western blot analysis using this antibody, we found that APPL1 phosphorylation at Ser401 is rapidly stimulated by insulin in C2C12 cells (Figure 6A) and in mouse skeletal muscle tissues (Figure 6B). The insulin-stimulated APPL1 Ser401 phosphorylation was significantly reduced in insulin target tissues of mice fed a high-fat diet compared to mice fed with normal chow, which was associated with an impaired PI3K signaling pathway (Figures 6C, S4C, and S4D). Together, these results indicate a correlation between APPL1 phosphorylation at Ser401 and insulin sensitivity in vivo.
Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.