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

J. Biol. Chem., Vol. 278, Issue 13, 11107-11114, March 28, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/13/11107    most recent M212541200v1 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 Dhar-Mascareño, M. Articles by Golde, D. W. Search for Related Content PubMed PubMed Citation Articles by Dhar-Mascareño, M. Articles by Golde, D. W. Social Bookmarking                      What's this?

Granulocyte-Macrophage Colony-stimulating Factor Signals for Increased Glucose Transport via Phosphatidylinositol 3-Kinase- and Hydrogen Peroxide-dependent Mechanisms^*

Manya Dhar-Mascareño^§, Jian Chen^§¶, Rong Hua Zhang, Juan M. Cárcamo, and David W. Golde^¶**

From the  Program in Molecular Pharmacology and Chemistry and the  Department of Clinical Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and the ^¶ Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, 10021

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates cellular glucose uptake by decreasing the apparent K_m for substrate transport through facilitative glucose transporters on the plasma membrane. Little is known about this signal transduction pathway and the role of the  subunit of the GM-CSF receptor (GMR) in modulating transporter activity. We examined the function of phosphatidylinositol 3-kinase (PI 3-kinase) in GM-CSF-stimulated glucose uptake and found that PI 3-kinase inhibitors, wortmannin and LY294002, completely blocked the GM-CSF-dependent increase of glucose uptake in Xenopus oocytes expressing the low affinity GMR and in human cells expressing the high affinity GMR complex. We identified a Src homology 3 domain-binding motif in GMR at residues 358-361 as a potential interaction site for the PI 3-kinase regulatory subunit, p85. Physical evidence for p85 binding to GMR was obtained by co-immunoprecipitation with antibodies to GMR and p85, and an GMR mutant with alteration of the Src homology 3 binding domain lost the ability to bind p85. Experiments with a construct eliminating most of the intracellular portion of GMR showed a 50% reduction in GM-CSF-stimulated glucose uptake with residual activity blocked by wortmannin. Searching for a proximally generated diffusible factor capable of activating PI 3-kinase, we identified hydrogen peroxide (H₂O₂), generated by ligand or antibody binding to GMR, as the initiating factor. Catalase treatment abrogated GM-CSF- or anti-GMR antibody-stimulated glucose uptake in GMR-expressing oocytes, and H₂O₂ activated PI 3-kinase and led to some stimulation of glucose uptake in uninjected oocytes. Human myeloid cell lines and primary explant human lymphocytes expressing high affinity GM-CSF receptors responded to GMR antibody with increased glucose uptake. These results identify the early events in the stimulation of glucose uptake by GM-CSF as involving local H₂O₂ generation and requiring PI 3-kinase activation. Our findings also provide a mechanistic explanation for signaling through the isolated  subunit of the GM-CSF receptor.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				G. J. DeYulia Jr., J. M. Carcamo, O. Borquez-Ojeda, C. C. Shelton, and D. W. Golde Hydrogen peroxide generated extracellularly by receptor-ligand interaction facilitates cell signaling PNAS, April 5, 2005; 102(14): 5044 - 5049. [Abstract] [Full Text] [PDF]

				A. B. Carter, L. A. Tephly, S. Venkataraman, L. W. Oberley, Y. Zhang, G. R. Buettner, D. R. Spitz, and G. W. Hunninghake High Levels of Catalase and Glutathione Peroxidase Activity Dampen H2O2 Signaling in Human Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 43 - 53. [Abstract] [Full Text] [PDF]

				R. B. Gaynor A role for extracellular matrix binding receptors in regulating hematopoietic growth factor signaling PNAS, November 25, 2003; 100(24): 13737 - 13738. [Full Text] [PDF]

				J. Chen, J. M. Carcamo, O. Borquez-Ojeda, H. Erdjument-Bromage, P. Tempst, and D. W. Golde From the Cover: The laminin receptor modulates granulocyte-macrophage colony-stimulating factor receptor complex formation and modulates its signaling PNAS, November 25, 2003; 100(24): 14000 - 14005. [Abstract] [Full Text] [PDF]