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

J. Biol. Chem., Vol. 280, Issue 42, 35545-35553, October 21, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/42/35545    most recent M505630200v1 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 Mitsuzuka, K. Articles by Hakomori, S. Search for Related Content PubMed PubMed Citation Articles by Mitsuzuka, K. Articles by Hakomori, S. Social Bookmarking                      What's this?

A Specific Microdomain ("Glycosynapse 3") Controls Phenotypic Conversion and Reversion of Bladder Cancer Cells through GM3-mediated Interaction of 31 Integrin with CD9^*

Koji Mitsuzuka, Kazuko Handa, Makoto Satoh, Yoichi Arai, and Senitiroh Hakomori1

From the Pacific Northwest Research Institute, Seattle, Washington 98122, the Department of Pathobiology, University of Washington, Seattle, Washington 98195, and the Department of Urology, Tohoku University School of Medicine, Sendai 980-8574, Japan

Cell motility is highly dependent on the organization and function of microdomains composed of integrin, proteolipid/tetraspanin CD9, and ganglioside (Ono, M., Handa, K., Sonnino, S., Withers, D. A., Nagai, H., and Hakomori, S. (2001) Biochemistry 40, 6414–6421; Kawakami, Y., Kawakami, K., Steelant, W. F. A., Ono, M., Baek, R. C., Handa, K., Withers, D. A., and Hakomori, S. (2002) J. Biol. Chem. 277, 34349–34358), later termed "glycosynapse 3" (Hakomori, S., and Handa, K. (2002) FEBS Lett. 531, 88–92, 2002). Human bladder cancer cell lines KK47 (noninvasive and nonmetastatic) and YTS1 (highly invasive and metastatic), both derived from transitional bladder epithelia, are very similar in terms of integrin composition and levels of tetraspanin CD9. Tetraspanin CD82 is absent in both. The major difference is in the level of ganglioside GM3, which is several times higher in KK47 than in YTS1. We now report that the GM3 level reflects glycosynapse function as follows: (i) a stronger interaction of integrin 3 with CD9 in KK47 than in YTS1; (ii) conversion of benign, low motility KK47 to invasive, high motility cells by depletion of GM3 by P4 (D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol) treatment or by knockdown of CD9 by the RNA interference method; (iii) reversion of high motility YTS1 to low motility phenotype like that of KK47 by exogenous GM3 addition, whereby the 3-to-CD9 interaction was enhanced; (iv) low GM3 level activated c-Src in YTS1 or in P4-treated KK47, and high GM3 level by exogenous addition caused Csk translocation into glycosynapse, with subsequent inhibition of c-Src activation; (v) inhibition of c-Src by "PP2" in YTS1 greatly reduced cell motility. Thus, GM3 in glycosynapse 3 plays a dual role in defining glycosynapse 3 function. One is by modulating the interaction of 3 with CD9; the other is by activating or inhibiting the c-Src activity, possibly through Csk translocation. High GM3 level decreases tumor cell motility/invasiveness, whereas low GM3 level enhances tumor cell motility/invasiveness. Oncogenic transformation and its reversion can be explained through the difference in glycosynapse organization.

Received for publication, May 23, 2005 , and in revised form, July 29, 2005.

^* This work was supported by NCI Grant R01 CA80054 (to S. H.) from 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 To whom correspondence should be addressed: Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122-4302. E-mail: hakomori{at}u.washington.edu.

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

This article has been cited by other articles:

				T. Takahashi, K. Murakami, M. Nagakura, H. Kishita, S. Watanabe, K. Honke, K. Ogura, T. Tai, K. Kawasaki, D. Miyamoto, et al. Sulfatide Is Required for Efficient Replication of Influenza A Virus J. Virol., June 15, 2008; 82(12): 5940 - 5950. [Abstract] [Full Text] [PDF]

				P. Mukherjee, A. C. Faber, L. M. Shelton, R. C. Baek, T. C. Chiles, and T. N. Seyfried Thematic Review Series: Sphingolipids. Ganglioside GM3 suppresses the proangiogenic effects of vascular endothelial growth factor and ganglioside GD1a J. Lipid Res., May 1, 2008; 49(5): 929 - 938. [Abstract] [Full Text] [PDF]

				A. R. Todeschini, J. N. Dos Santos, K. Handa, and S.-i. Hakomori Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway PNAS, February 12, 2008; 105(6): 1925 - 1930. [Abstract] [Full Text] [PDF]

				X.-q. Wang, Q. Yan, P. Sun, J.-W. Liu, L. Go, S. M. McDaniel, and A. S. Paller Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-{alpha} Activation Requires CD82, Caveolin-1, and Ganglioside Cancer Res., October 15, 2007; 67(20): 9986 - 9995. [Abstract] [Full Text] [PDF]

				Z. Vukelic, S. Kalanj-Bognar, M. Froesch, L. Bindila, B. Radic, M. Allen, J. Peter-Katalinic, and A. D. Zamfir Human gliosarcoma-associated ganglioside composition is complex and distinctive as evidenced by high-performance mass spectrometric determination and structural characterization Glycobiology, May 1, 2007; 17(5): 504 - 515. [Abstract] [Full Text] [PDF]

				A. R. Todeschini, J. N. Dos Santos, K. Handa, and S.-i. Hakomori Ganglioside GM2-Tetraspanin CD82 Complex Inhibits Met and Its Cross-talk with Integrins, Providing a Basis for Control of Cell Motility through Glycosynapse J. Biol. Chem., March 16, 2007; 282(11): 8123 - 8133. [Abstract] [Full Text] [PDF]

				Z. Wang, Z. Sun, A. V. Li, and K. J. Yarema Roles for UDP-GlcNAc 2-Epimerase/ManNAc 6-Kinase outside of Sialic Acid Biosynthesis: MODULATION OF SIALYLTRANSFERASE AND BiP EXPRESSION, GM3 AND GD3 BIOSYNTHESIS, PROLIFERATION, AND APOPTOSIS, AND ERK1/2 PHOSPHORYLATION J. Biol. Chem., September 15, 2006; 281(37): 27016 - 27028. [Abstract] [Full Text] [PDF]