Fibroblasts require protein kinase C activation to respond to hyaluronan with increased locomotion

Hall, Christine; Collis, Lisa; A, Jing Bo; Lange, L; McNicol, Andrew; Gerrard, John M.; Turley, Eva A.

doi:10.1016/s0945-053x(01)00133-0

Cited by 41 publications

(35 citation statements)

References 45 publications

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“…For example, RHAMM is required for activation of signaling pathways through IL-1␤ and TNF-␣, such as erk, and AP-1 (14,19). RHAMM also binds to calmodulin (16), regulates connexin expression (43), and promotes formation of diacylgycerol in response to hyaluronan, linking this hyaladherin to phospholipase C␥ (44).…”

Section: Discussionmentioning

confidence: 99%

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

Nedvetzki

Gonen

Assayag

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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182

175

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We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined

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Section: Discussionmentioning

confidence: 99%

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

Nedvetzki

Gonen

Assayag

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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182

175

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“…CD44 was shown previously to promote motility of breast cancer cell lines, and Rhamm was shown to promote motility of fibroblasts and immune cells (9,45,65,71,72). Therefore, we compared the relative roles played by these HA receptors in the motility of the fibroblast-like MDA-MB-231 and Ras-MCF10A tumor cells with the epithelial MCF7 and MCF10A cells, using function-blocking antibodies specific to each of these receptors.…”

Section: Invasive Breast Tumor Cell Lines Produce Endogenous Hamentioning

confidence: 99%

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

Hamilton

Fard

Paiwand

et al. 2007

Journal of Biological Chemistry

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242

227

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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.Breast cancer invasion and progression involves a motile cell phenotype, which is under complex regulation by growth factors/cytokines and extracellular matrix (ECM) 4 components within the tumor microenvironment (1, 2). Motogenic signaling in tumor cells can be stimulated by both paracrine and autocrine factors; the latter decrease the requirement of invasive carcinomas for stromal support and are often associated with tumor progression (3-6). Hyaluronan (HA) (an anionic polymer of repeating units of glucuronic acid and N-acetylglucosamine) is one stromal ECM component that is associated with breast cancer progression (7,8). In culture, HA stimulates breast cancer cell motility (9 -11), pointing to a possible important role of this glycosaminoglycan in breast cancer cell invasion in vivo.

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“…Since then, small amounts (nanograms) of hyaluronan have been shown to activate a variety of protein tyrosine and serine/threonine kinases. These include the non-receptor protein tyrosine kinase Src (5, 6), HER2/Neu receptor (7), focal adhesion kinase (4, 8 -10), protein kinase C (11,12), and MAP 1 kinases (9,10). Likely as a consequence of regulating these kinases, hyaluronan promotes expression of specific cytokines and proteins involved in extracellular matrix remodeling (e.g.…”

mentioning

confidence: 99%

Signaling Properties of Hyaluronan Receptors

Turley¹,

Noble²,

Bourguignon³

2002

Journal of Biological Chemistry

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959

843

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Fibroblasts require protein kinase C activation to respond to hyaluronan with increased locomotion

Cited by 41 publications

References 45 publications

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy

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

Signaling Properties of Hyaluronan Receptors

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