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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.

ABSTRACT: 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.

SUBMITTER: Hamilton SR

PROVIDER: S-EPMC2949353 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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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.

Hamilton Sara R SR Fard Shireen F SF Paiwand Frouz F FF Tolg Cornelia C Veiseh Mandana M Wang Chao C McCarthy James B JB Bissell Mina J MJ Koropatnick James J Turley Eva A EA

The Journal of biological chemistry 20070328 22

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/invasiv ...[more]

PMID: 17392272

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Project description:Acute lung injury results in early inflammation and respiratory distress, and later fibrosis. The glycosaminoglycan hyaluronan (HA) and the Receptor for Hyaluronan-Mediated Motility (RHAMM, CD168) have been implicated in the response to acute lung injury. We hypothesized that, compared to wild type (WT) mice, RHAMM knockout (KO) mice would be protected from, whereas mice with macrophage-specific transgenic overexpression of RHAMM (TG) would have worse inflammation, respiratory distress and fibrosis after intratracheal (IT) bleomycin. Compared to WT mice, 10?days after IT bleomycin, RHAMM KO mice had less weight loss, less increase in respiratory rate, and fewer CD45+ cells in the lung. At day 28, compared to injured WT animals, injured RHAMM KO mice had lower M1 macrophage content, as well as decreased fibrosis as determined by trichrome staining, Ashcroft scores and lung HPO content. Four lines of transgenic mice with selective overexpression of RHAMM in macrophages were generated using the Scavenger Receptor A promoter driving a myc-tagged full length RHAMM cDNA. Baseline expression of RHAMM and CD44 was the same in WT and TG mice. By flow cytometry, TG bone marrow-derived macrophages (BMDM) had increased cell surface RHAMM and myc, but equal CD44 expression. TG BMDM also had 2-fold increases in both chemotaxis to HA and proliferation in fetal bovine serum. In TG mice, increased inflammation after thioglycollate-induced peritonitis was restricted to macrophages and not neutrophils. For lung injury studies, non-transgenic mice given bleomycin had respiratory distress with increased respiratory rates from day 7 to 21. However, TG mice had higher respiratory rates from 4?days after bleomycin and continued to increase respiratory rates up to day 21. At 21?days after IT bleomycin, TG mice had increased lung macrophage accumulation. Lavage HA concentrations were 6-fold higher in injured WT mice, but 30-fold higher in injured TG mice. At 21?days after IT bleomycin, WT mice had developed fibrosis, but TG mice showed exaggerated fibrosis with increased Ashcroft scores and HPO content. We conclude that RHAMM is a critical component of the inflammatory response, respiratory distress and fibrosis after acute lung injury. We speculate that RHAMM is a potential therapeutic target to limit the consequences of acute lung injury.

Project description:Hyaluronic acid (HA) is an extracellular matrix (ECM) component that has been shown to play a significant role in regulating muscle cell behavior during repair and regeneration. For instance, ECM remodeling after muscle injury involves an upregulation in HA expression that is coupled with skeletal muscle precursor cell recruitment. However, little is known about the role of HA during skeletal muscle development. To gain insight into the way in which HA mediates embryonic myogenesis, we first determined the spatial distribution and gene expression of CD44, RHAMM and other HA related proteins in embryonic day (E)10.5 to E12.5 murine forelimbs. While HA and CD44 expression remained high, RHAMM decreased at both the protein (via immunohistochemistry) and RNA (via qPCR) levels. Next, we determined that 4-methylumbelliferone-mediated knockdown of HA synthesis inhibited the migration and proliferation of E11.5/E12.5 forelimb-derived cells. Then, the influence of CD44 and RHAMM on myoblast and connective tissue cell behavior was investigated using antibodies against these receptors. Anti-RHAMM, but not anti-CD44, significantly decreased the total distance myogenic progenitors migrated over 24?h, whereas both inhibited connective tissue cell migration. In contrast, anti-CD44 inhibited the proliferation of connective tissue cells and muscle progenitors, but anti-RHAMM had no effect. However, when myoblasts and connective tissue cells were depleted of CD44 and RHAMM by shRNA, motility and proliferation were significantly inhibited in both cells indicating that blocking cell surface-localized CD44 and RHAMM does not have as pronounced effect as global shRNA-mediated depletion of these receptors. These results show, for the first time, the distribution and activity of RHAMM in the context of skeletal muscle. Furthermore, our data indicate that HA, through interactions with CD44 and RHAMM, promotes myogenic progenitor migration and proliferation. Confirmation of the role of HA and its receptors in directing myogenesis will be useful for the design of regenerative therapies that aim to promote the restoration of damaged or diseased muscle.

Dataset Information

The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells.

Publications

The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells.

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