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J. Biol. Chem., Vol. 282, Issue 22, 16667-16680, June 1, 2007

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The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells^*

Sara R. Hamilton, Shireen F. Fard¹, Frouz F. Paiwand¹, Cornelia Tolg¹, Mandana Veiseh^¶, Chao Wang, James B. McCarthy^||, Mina J. Bissell^¶2, James Koropatnick, and Eva A. Turley³

From the London Regional Cancer Program, London Health Sciences Centre, and The University of Western Ontario, London, Ontario N6A 4L6, Canada, Department of Cardiovascular Research, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, ^||Department of Laboratory Medicine and Pathology and University of Minnesota Comprehensive Cancer Center, Minneapolis, Minnesota 55455, and ^¶Division of Life Sciences, Lawrence Berkeley National Laboratories, Berkeley California 94710

CD44 is an integral hyaluronan receptor that can promote or inhibit motogenic signaling in tumor cells. Rhamm is a nonintegral cell surface hyaluronan receptor (CD168) and intracellular protein that promotes cell motility in culture. Here we describe an autocrine mechanism utilizing cell surface Rhamm-CD44 interactions to sustain rapid basal motility in invasive breast cancer cell lines that requires endogenous hyaluronan synthesis and the formation of Rhamm-CD44-ERK1,2 complexes. Motile/invasive MDA-MB-231 and Ras-MCF10A cells produce more endogenous hyaluronan, cell surface CD44 and Rhamm, an oncogenic Rhamm isoform, and exhibit more elevated basal activation of ERK1,2 than less invasive MCF7 and MCF10A breast cancer cells. Furthermore, CD44, Rhamm, and ERK1,2 uniquely co-immunoprecipitate and co-localize in MDA-MB-231 and Ras-MCF10A cells. Combinations of anti-CD44, anti-Rhamm antibodies, and a MEK1 inhibitor (PD098059) had less-than-additive blocking effects, suggesting the action of all three proteins on a common motogenic signaling pathway. Collectively, these results show that cell surface Rhamm and CD44 act together in a hyaluronan-dependent autocrine mechanism to coordinate sustained signaling through ERK1,2, leading to high basal motility of invasive breast cancer cells. Therefore, an effect of CD44 on tumor cell motility may depend in part on its ability to partner with additional proteins, such as cell surface Rhamm.

Received for publication, March 9, 2007 , and in revised form, March 26, 2007.

^* This work was supported by Canadian Institutes of Health Research Grants MOP-57694 (to E. A. T.) and MOP-62836 (to J. K.) and Fellowship UST-63811 (to S. R. H.); the Breast Cancer Translational Unit at the London Regional Cancer Program, Breast Cancer Society of Canada salary support (to E. A. T.) and fellowships (to C. T., S. F. F., and S. R. H.); United States Department of Defense Grants DOD-PC050959 (to J. B. M. and E. A. T.), BCRP-CDMRP (to E. A. T.), and BC044087 (to M. J. B.); the United States Department of Energy, Office of Biological and Environmental Research (to M. J. B.); and NCI, National Institutes of Health (to M. J. B. with Z. Werb). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. I.

¹ These authors contributed equally and are listed in alphabetical order.

² Recipient of an Innovator award from the United States Department of Defense Breast Cancer Program and a Distinguished Scientist fellowship from the United States Department of Energy.

³ To whom correspondence should be addressed: London Regional Cancer Program, Cancer Research Laboratories, Rm. A4-931, 790 Commissioners Rd. E, London, Ontario N6A 4L6, Canada. Tel.: 519-685-8600, ext. 53677; Fax: 519-685-8616; E-mail: eva.turley{at}lhsc.on.ca.

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