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

J. Biol. Chem., Vol. 278, Issue 27, 25014-25023, July 4, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/27/25014    most recent M211867200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahboubi, K. Articles by Pober, J. S. Search for Related Content PubMed PubMed Citation Articles by Mahboubi, K. Articles by Pober, J. S. Social Bookmarking                      What's this?

Desensitization of Signaling by Oncostatin M in Human Vascular Cells Involves Cytoplasmic Tyr Residue 759 in gp130 but Is Not Mediated by Either Src Homology 2 Domain-containing Tyrosine Phosphatase 2 or Suppressor of Cytokine Signaling 3^*

Keyvan Mahboubi , Nancy C. Kirkiles-Smith , Jim Karras  and Jordan S. Pober  ¶

From the Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510 and the Molecular and Cellular Pharmacology, ISIS Pharmaceuticals, Carlsbad, California 92008

Oncostatin M (OnM) signals through cell surface receptors, which utilize the gp130 subunit. In cultured human umbilical vein endothelial cells (HUVEC), OnM transiently elevates mRNA encoding for suppressor of cytokine signaling-3 (SOCS-3). By 1 h of OnM treatment, HUVEC become refractory to the restimulation by OnM, measured as failure to reinduce SOCS-3 mRNA. OnM-induced desensitization also prevents responses to other gp130-signaling cytokines (e.g. leukemia inhibitory factor and interleukin 11). OnM treatment does not affect gp130 expression levels and desensitizes signaling mediated by a transduced chimeric receptor containing extracellular domains of platelet-derived growth factor receptor- (PDGFR) and the cytoplasmic region of gp130. Interestingly, a chimeric PDGFR-gp130 mutant receptor, in which intracellular Tyr residue 759 of gp130 is replaced by a Phe residue, mediates prolonged signaling and is not cross-desensitized by OnM. Phospho-Tyr⁷⁵⁹ is the binding site for both SOCS-3 and for Src homology domain 2-containing tyrosine phosphatase 2 (SHP-2). In human aortic smooth muscle cells, neither prevention of SOCS-3 protein induction, using STAT3 or SOCS-3 antisense, nor prevention of SHP-2 expression, also with antisense, ablates desensitization. These data suggest that desensitization of vascular cells to OnM is mediated in trans and involves Tyr residue 759 in gp130 but is not mediated by either SOCS-3 or SHP-2, the only two proteins currently known to bind to gp130 at this site.

Received for publication, November 21, 2002 , and in revised form, April 10, 2003.

^* This work was supported by National Institutes of Health Grants F32-HL10275 (to K. M.), HL36003, and 62188 (to J. S. P.), and by a grant from ISIS Pharmaceuticals (to J. S. P). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Boyer Center for Molecular Medicine, Room 454, 295 Congress Ave., New Haven, CT 06510, Tel.: 203-737-2292; Fax: 203-737-2293; E-mail: jordan.pober{at}yale.edu.

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

This article has been cited by other articles:

				M. Liu, M. S. Kluger, A. D'Alessio, G. Garcia-Cardena, and J. S. Pober Regulation of Arterial-Venous Differences in Tumor Necrosis Factor Responsiveness of Endothelial Cells by Anatomic Context Am. J. Pathol., April 1, 2008; 172(4): 1088 - 1099. [Abstract] [Full Text] [PDF]

				D. A. Rao, K. J. Tracey, and J. S. Pober IL-1{alpha} and IL-1beta Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response J. Immunol., November 15, 2007; 179(10): 6536 - 6546. [Abstract] [Full Text] [PDF]

				C. Stross, S. Radtke, T. Clahsen, C. Gerlach, R. Volkmer-Engert, F. Schaper, P. C. Heinrich, and H. M. Hermanns Oncostatin M Receptor-mediated Signal Transduction Is Negatively Regulated by SOCS3 through a Receptor Tyrosine-independent Mechanism J. Biol. Chem., March 31, 2006; 281(13): 8458 - 8468. [Abstract] [Full Text] [PDF]

				S. Zvonic, J. E. Baugh Jr., P. Arbour-Reily, R. L. Mynatt, and J. M. Stephens Cross-talk among gp130 Cytokines in Adipocytes J. Biol. Chem., October 7, 2005; 280(40): 33856 - 33863. [Abstract] [Full Text] [PDF]

				J. Choi, J. Walker, S. Boichuk, N. Kirkiles-Smith, N. Torpey, J. S. Pober, and L. Alexander Human Endothelial Cells Enhance Human Immunodeficiency Virus Type 1 Replication in CD4+ T Cells in a Nef-Dependent Manner In Vitro and In Vivo J. Virol., January 1, 2005; 79(1): 264 - 276. [Abstract] [Full Text] [PDF]

				N. Torpey, S. E. Maher, A. L. M. Bothwell, and J. S. Pober Interferon {alpha} but Not Interleukin 12 Activates STAT4 Signaling in Human Vascular Endothelial Cells J. Biol. Chem., June 18, 2004; 279(25): 26789 - 26796. [Abstract] [Full Text] [PDF]

				N. C. Kirkiles-Smith, K. Mahboubi, J. Plescia, J. M. McNiff, J. Karras, J. S. Schechner, D. C. Altieri, and J. S. Pober IL-11 Protects Human Microvascular Endothelium from Alloinjury In Vivo by Induction of Survivin Expression J. Immunol., February 1, 2004; 172(3): 1391 - 1396. [Abstract] [Full Text] [PDF]