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Papers In Press, published online ahead of print August 15, 2005
Department of Pathobiology, University of Washington at Seattle, Seattle, WA 98122-4302
Corresponding Author: hakomori{at}u.washington.edu
Cell motility is highly dependent on organization and function of microdomains composed of integrin, proteolipid/ tetraspanin CD9, and ganglioside (Ono M, Handa K, Sonnino S, et al, Biochemistry 40: 6414-21, 2001; Kawakami Y, Kawakami K, Steelant W, et al, JBC 277: 34349-58, 2002), later termed "glycosynapse 3" (Hakomori S, Handa K, FEBS Lett 531: 88-92, 2002). Human bladder cancer cell lines KK47 (non-invasive, non-metastatic) and YTS1 (highly invasive, 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 level of ganglioside GM3, which is several times higher in KK47 than in YTS1. We now report that GM3 level reflects glycosynapse function, as shown by: (i) a stronger interaction of integrin
J. Biol. Chem, 10.1074/jbc.M505630200
Submitted on May 23, 2005
Revised on July 29, 2005
Accepted on August 15, 2005
A specific microdomain ("Glycosynapse 3") controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of
3
1 integrin with CD9
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 RNAi 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 cSrc in YTS1 or in P4-treated KK47; high GM3 level by exogenous addition caused Csk translocation into glycosynapse, with subsequent inhibition of cSrc activation; (v) inhibition of cSrc by "PP2" in YTS1 greatly reduced cell motility. Thus, GM3 in glycosynapse 3 plays a dual role in defining glycosynapse 3 function. One is modulating interaction of 3 with CD9; the other is activating or inhibiting cSrc 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 difference in glycosynapse organization.
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