APS-mediated Ubiquitination of the Insulin Receptor Enhances its Internalization, but does not Induce its Degradation

APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin sensitivity, and that this enhanceme...

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Bibliographic Details
Published in:Endocrine Journal 2007, Vol.54(1), pp.77-88
Main Authors: KISHI, Kazuhiro, MAWATARI, Kazuaki, SAKAI-WAKAMATSU, Kikuko, YUASA, Tomoyuki, WANG, Miao, OGURA-SAWA, Makoto, NAKAYA, Yutaka, HATAKEYAMA, Shigetsugu, EBINA, Yousuke
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Animals
APS
Cbl
CHO Cells
Cricetinae
Cricetulus
Humans
Insulin - metabolism
Insulin receptor
Internalization
Mice
Multi-ubiquitination
Protein Processing, Post-Translational
Protein Transport
Receptor, Insulin - genetics
Receptor, Insulin - metabolism
Signal Transduction - genetics
Transfection
Ubiquitin - metabolism
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Summary:APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin sensitivity, and that this enhancement is possibly due to increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has so far been controversial. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of the insulin receptor (IR) in CHO cells overexpressing the IR. APS-mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. This finding shows one of the pleiotropic functions of APS in insulin signaling.
ISSN:0918-8959
1348-4540
DOI:10.1507/endocrj.K06-056