Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 26087-26093 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 287 |
| Issue number | 31 |
| DOIs | |
| State | Published - Jul 27 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
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. / Liu, Meilian; Zhou, Lijun; Wei, Li; Villarreal, Ricardo; Yang, Xin; Hu, Derong; Riojas, Ramon A.; Holmes, Bekke M.; Langlais, Paul R; Lee, Hakjoo; Dong, Lily Q.
In: Journal of Biological Chemistry, Vol. 287, No. 31, 27.07.2012, p. 26087-26093.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Liu, Meilian
AU - Zhou, Lijun
AU - Wei, Li
AU - Villarreal, Ricardo
AU - Yang, Xin
AU - Hu, Derong
AU - Riojas, Ramon A.
AU - Holmes, Bekke M.
AU - Langlais, Paul R
AU - Lee, Hakjoo
AU - Dong, Lily Q.
PY - 2012/7/27
Y1 - 2012/7/27
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84864390268&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.372292
DO - 10.1074/jbc.M112.372292
M3 - Article
VL - 287
SP - 26087
EP - 26093
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 31
ER -