HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berhanu, P. Articles by Ciaraldi, T. P. Search for Related Content PubMed PubMed Citation Articles by Berhanu, P. Articles by Ciaraldi, T. P. Social Bookmarking                      What's this?

Volume 272, Number 36, Issue of September 5, 1997 pp. 22884-22890
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Insulin Signal Transduction by a Mutant Human Insulin Receptor Lacking the NPEY Sequence
EVIDENCE FOR AN ALTERNATE MITOGENIC SIGNALING PATHWAY THAT IS INDEPENDENT OF Shc PHOSPHORYLATION

(Received for publication, March 11, 1997, and in revised form, June 17, 1997)

Paulos Berhanu , Celia Anderson , Matt Hickman ^¶ and Theodore P. Ciaraldi ^¶

From the  Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 and the ^¶ Department of Medicine, University of California, San Diego, California 92093

The cytoplasmic juxtamembrane domain of the human insulin receptor (hIR) contains a single copy of the tetrameric amino acid sequence Asn-Pro-Glu-Tyr (NPEY) (residues 969-972 in the exon 11-containing B-isoform), which exists in the context of NPXY. In this study, we examined the role of NPEY⁹⁷² in mediating insulin signal transduction and cellular biological effects. Transfected Chinese hamster ovary cell lines expressing either the wild-type hIR-B isoform (hIR·WT) or a mutant receptor lacking the NPEY⁹⁷² sequence (hIRNPEY) and control Chinese hamster ovary·Neo cells were used to comparatively analyze the following insulin effects: in vivo receptor tyrosine autophosphorylation and kinase activity, signal transduction to downstream signaling molecules, and stimulation of glycogen and DNA synthesis. The results showed that in comparison to hIR·WT, the hIRNPEY mutant demonstrated the following: (a) normal insulin-mediated receptor tyrosine phosphorylation, but ~50% reduction in phosphorylation of p185-(insulin receptor substrate-1) and binding of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase), (b) an enhanced stimulation of PI 3-kinase enzymatic activity, (c) a complete inability to phosphorylate Shc, (d) minimal impairment of insulin sensitivity for glycogen synthesis, and (e) an augmented response to insulin-stimulated DNA synthesis via a high capacity, low sensitivity pathway. These results demonstrate the following: 1) the NPEY⁹⁷² sequence is important but not absolutely essential for coupling of hIR kinase to insulin receptor substrate-1 and p85 or for mediating insulin's metabolic and mitogenic effects, 2) the NPEY⁹⁷² sequence is necessary for Shc phosphorylation, and 3) the absence of Shc phosphorylation releases the constraints on maximal insulin-stimulated mitogenic response, thus indicating that alternate signaling pathway(s) exist for this insulin action. This alternate pathway appears to be associated with enhanced activation of PI 3-kinase and is of high capacity and low sensitivity.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Bose, M A. Farah, H.-C. Jung, J.-H. Lee, and Y. Kim Molecular mechanism of bis(maltolato)oxovanadium(IV)-induced insulin signaling in 3T3-L1 and IM9 cells: impact of dexamethasone J. Mol. Endocrinol., June 1, 2007; 38(6): 627 - 649. [Abstract] [Full Text] [PDF]

				T. P. Ciaraldi, S. A. Phillips, L. Carter, V. Aroda, S. Mudaliar, and R. R. Henry Effects of the Rapid-Acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle Cells: Comparisons with Insulin and Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5551 - 5558. [Abstract] [Full Text] [PDF]

				T.-C. Meng, D. A. Buckley, S. Galic, T. Tiganis, and N. K. Tonks Regulation of Insulin Signaling through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B J. Biol. Chem., September 3, 2004; 279(36): 37716 - 37725. [Abstract] [Full Text] [PDF]

				T. P. Ciaraldi, L. Carter, G. Seipke, S. Mudaliar, and R. R. Henry Effects of the Long-Acting Insulin Analog Insulin Glargine on Cultured Human Skeletal Muscle Cells: Comparisons to Insulin and IGF-I J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5838 - 5847. [Abstract] [Full Text] [PDF]

				M. L. Goalstone, J. W. Leitner, P. Berhanu, P. M. Sharma, J. M. Olefsky, and B. Draznin Insulin Signals to Prenyltransferases via the Shc Branch of Intracellular Signaling J. Biol. Chem., April 13, 2001; 276(16): 12805 - 12812. [Abstract] [Full Text] [PDF]