Phosphorylation of adaptor protein containing pleckstrin homology domain, phosphotyrosinebinding domain, and leucine zipper motif 1 (APPL1) at Ser 430 mediates endoplasmic reticulum (ER) stress-induced insulin resistance in hepatocytes

Meilian Liu, Lijun Zhou, Li Wei, Ricardo Villarreal, Xin Yang, Derong Hu, Ramon A. Riojas, Bekke M. Holmes, Paul R. Langlais, Hakjoo Lee, Lily Q. Dong

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12 Scopus citations


APPL1 is an adaptor protein that plays a critical role in regulating adiponectin and insulin signaling. However, how APPL1 is regulated under normal and pathological conditions remains largely unknown. In this study, we show that APPL1 undergoes phosphorylation at Ser430 and that this phosphorylation is enhanced in the liver of obese mice displaying insulin resistance. In cultured mouse hepatocytes, APPL1 phosphorylation at Ser 430 is stimulated by phorbol 12-myristate 13-acetate, an activator of classicPKCisoforms, and by the endoplasmic reticulum (ER) stress inducer, thapsigargin. Overexpression of wild-type but not dominant negative PKCα increases APPL1 phosphorylation at Ser430 in mouse hepatocytes. In addition, suppressing PKCα expression by shRNA in hepatocytes reduces ER stressinduced APPL1 phosphorylation at Ser430 as well as the inhibitory effect of ER stress on insulin-stimulated Akt phosphorylation. Consistent with a negative regulatory role of APPL1 phosphorylation at Ser 430 in insulin signaling, overexpression of APPL1S430D but not APPL1S430A impairs the potentiating effect of APPL1 on insulin-stimulated Akt phosphorylation at Thr308. Taken together, our results identify APPL1 as a novel target in ER stress-induced insulin resistance and PKCα as the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser430.

Original languageEnglish (US)
Pages (from-to)26087-26093
Number of pages7
JournalJournal of Biological Chemistry
Issue number31
StatePublished - Jul 27 2012
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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