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

J. Biol. Chem., Vol. 282, Issue 20, 14816-14826, May 18, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/20/14816    most recent M611430200v1 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 Zhu, T.-N. Articles by Bernier, M. Search for Related Content PubMed PubMed Citation Articles by Zhu, T.-N. Articles by Bernier, M. Social Bookmarking                      What's this?

Filamin A-mediated Down-regulation of the Exchange Factor Ras-GRF1 Correlates with Decreased Matrix Metalloproteinase-9 Expression in Human Melanoma Cells^*

Tie-Nian Zhu¹², Hua-Jun He¹³, Sutapa Kole, Theresa D'Souza, Rachana Agarwal, Patrice J. Morin, and Michel Bernier⁴

From the Diabetes Section, Laboratory of Clinical Investigation and Laboratory of Cellular and Molecular Biology, NIA, National Institutes of Health, Baltimore, Maryland 21224

The actin-binding protein filamin A (FLNa) is associated with diverse cellular processes such as cell motility and signaling through its scaffolding properties. Here we examine the effect of FLNa on the regulation of signaling pathways that control the expression of matrix metalloproteinases (MMPs). The lack of FLNa in human M2 melanoma cells was associated with constitutive and phorbol ester-induced expression and secretion of active MMP-9 in the absence of MMP-2 up-regulation. M2 cells displayed stronger MMP-9 production and activity than their M2A7 counterparts where FLNa had been stably reintroduced. Using an MMP-9 promoter construct (pMMP-9-Luc), in vitro kinase assays, and genetic and pharmacological approaches, we demonstrate that FLNa mediated transcriptional down-regulation of pMMP-9-Luc by suppressing the constitutive hyperactivity of the Ras/MAPK extracellular signal-regulated kinase (ERK) cascade. Experimental evidence indicated that this phenomenon was associated with destabilization and ubiquitylation of Ras-GRF1, a guanine nucleotide exchange factor that activates H-Ras by facilitating the release of GDP. Ectopic expression of Ras-GRF1 was accompanied by ERK activation and elevated levels of MMP-9 in M2A7 cells, whereas a catalytically inactive dominant negative Ras-GRF1, which prevented ERK activation, reduced MMP-9 expression in M2 cells. Our results indicate that expression of FLNa regulates constitutive activation of the Ras/ERK pathway partly through a Ras-GRF1 mechanism to modulate the production of MMP-9.

Received for publication, December 13, 2006 , and in revised form, February 26, 2007.

^* This research was supported by the Intramural Research Program of the NIA, National Institutes of Health. 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.

¹ These authors contributed equally to this work.

² Present address: Dept. of Endocrinology, Fourth Hospital, Hebei Medical University, 5 Jiankang Road, Shijiazhuang, Hebei 050011, P.R. China.

³ Present address: Biochemical Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899.

⁴ To whom correspondence should be addressed: Diabetes Section, National Institute on Aging, Box 23, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Tel.: 410-558-8199; Fax: 410-558-8381; E-mail: Bernierm{at}mail.nih.gov.

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

This article has been cited by other articles:

				J. L. Fiori, T.-N. Zhu, M. P. O'Connell, K. S. Hoek, F. E. Indig, B. P. Frank, C. Morris, S. Kole, J. Hasskamp, G. Elias, et al. Filamin A Modulates Kinase Activation and Intracellular Trafficking of Epidermal Growth Factor Receptors in Human Melanoma Cells Endocrinology, June 1, 2009; 150(6): 2551 - 2560. [Abstract] [Full Text] [PDF]

				Y. Xie, S. Kole, P. Precht, M. J. Pazin, and M. Bernier S-Glutathionylation Impairs Signal Transducer and Activator of Transcription 3 Activation and Signaling Endocrinology, March 1, 2009; 150(3): 1122 - 1131. [Abstract] [Full Text] [PDF]