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

• Published in: The Journal of biological chemistry Vol. 282; no. 22; pp. 16667 - 16680
• Main Authors: Hamilton, Sara R., Fard, Shireen F., Paiwand, Frouz F., Tolg, Cornelia, Veiseh, Mandana, Wang, Chao, McCarthy, James B., Bissell, Mina J., Koropatnick, James, Turley, Eva A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2007; American Society for Biochemistry and Molecular Biology
• Subjects: Antibodies, Monoclonal - pharmacology; Autocrine Communication - drug effects; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Extracellular Matrix Proteins - antagonists & inhibitors; Extracellular Matrix Proteins - metabolism; Female; Flavonoids - pharmacology; Humans; Hyaluronan Receptors - metabolism; Hyaluronic Acid - biosynthesis; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitosis - drug effects; Multiprotein Complexes - metabolism; Neoplasm Invasiveness; Neoplasm Proteins - metabolism; Protein Isoforms - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M702078200

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.