Signaling Properties of Hyaluronan Receptors

In 1979, hyaluronan was demonstrated to bind specifically and with high affinity to intact cells (1Underhill C.B. Toole B.P. J. Cell Biol. 1979; 82: 475-484Crossref PubMed Scopus (167) Google Scholar), and in 1980, it was shown to enhance cell motility on two-dimensional culture surfaces where the hydrodynamic properties of hyaluronan were not necessary to open spaces for cells to move into (2Turley E.A. Differentiation. 1980; 17: 93-103Crossref PubMed Scopus (28) Google Scholar). These two demonstrations raised the possibility that hyaluronan had the potential to directly modify cell behavior. In 1989, hyaluronan was shown to promote protein tyrosine phosphorylation cascades (3Turley E.A. J. Biol. Chem. 1989; 264: 8951-8955Abstract Full Text PDF PubMed Google Scholar) that were later proven to be required for hyaluronan-mediated motility on planar culture surfaces (4Hall C.L. Wang C. Lange L.A. Turley E.A. J. Cell Biol. 1994; 126: 575-588Crossref PubMed Scopus (226) Google Scholar). 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 (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar, 6Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2001; 276: 7327-7333Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar), HER2/Neu receptor (7Bourguignon L.Y.W. Zhu H.B. Chu A. Zhang L. Hung M.C. J. Biol. Chem. 1997; 272: 27913-27918Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar), focal adhesion kinase (4Hall C.L. Wang C. Lange L.A. Turley E.A. J. Cell Biol. 1994; 126: 575-588Crossref PubMed Scopus (226) Google Scholar, 8Hall C.L. Yang B. Yang X. Zhang S. Turley M. Samuel S. Lange L.A. Wang C. Curpen G.D. Savani R.C. Greenberg A.H. Turley E.A. Cell. 1995; 82: 19-26Abstract Full Text PDF PubMed Scopus (269) Google Scholar, 9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 10Lokeshwar V.B. Selzer M.G. J. Biol. Chem. 2000; 275: 27641-27649Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar), protein kinase C (11Hall C.L. Collis L. Lange L. McNicol A. Gerrard J.M. Turley E.A. Matrix Biol. 2001; 20: 183-192Crossref PubMed Scopus (39) Google Scholar, 12Slevin M. Krupinski J. Kumar S. Gaffney J. Lab. Invest. 1998; 78: 987-1003PubMed Google Scholar), and MAP 1The abbreviations used are:MAPmitogen-activated proteinHAS2hyaluronan synthase 2ROKRho kinaseERMezrin/radixin/moesinPIP2phosphatidylinositol 4,5-bisphosphatePDGFplatelet-derived growth factorRHAMMreceptor for hyaluronan-mediated motility kinases (9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 10Lokeshwar V.B. Selzer M.G. J. Biol. Chem. 2000; 275: 27641-27649Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Likely as a consequence of regulating these kinases, hyaluronan promotes expression of specific cytokines and proteins involved in extracellular matrix remodeling (e.g. Ref. 13Horton M.R. McKee C.M. Bao C. Liao F. Farber J.M. Hodge-DuFour J. Pure E. Oliver B.L. Wight T.M. Noble P.W. J. Biol. Chem. 1998; 273: 35088-35094Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). mitogen-activated protein hyaluronan synthase 2 Rho kinase ezrin/radixin/moesin phosphatidylinositol 4,5-bisphosphate platelet-derived growth factor receptor for hyaluronan-mediated motility The study of murine cardiac cells derived from hyaluronan synthase 2 (HAS2) knockout mice has provided the most convincing evidence for a signaling capability of hyaluronan (14Camenisch T.D. Spicer A.P. Brehm-Gibson T. Biesterfeldt J. Augustine M.L. Calabro A., Jr. Kubalak S. Klewer S.E. McDonald J.A. J. Clin. Invest. 2000; 106: 349-360Crossref PubMed Scopus (729) Google Scholar). HAS2−/− cardiac cells do not undergo an endothelial-mesenchymal transformation associated with migration from tissue explants whereas wild-type cells do (14Camenisch T.D. Spicer A.P. Brehm-Gibson T. Biesterfeldt J. Augustine M.L. Calabro A., Jr. Kubalak S. Klewer S.E. McDonald J.A. J. Clin. Invest. 2000; 106: 349-360Crossref PubMed Scopus (729) Google Scholar). However, the addition of nanogram amounts of exogenous hyaluronan “rescues” knockout cells. Furthermore, a dominant negative mutant of the small GTPase, Ras, blocks the effects of exogenous hyaluronan (14Camenisch T.D. Spicer A.P. Brehm-Gibson T. Biesterfeldt J. Augustine M.L. Calabro A., Jr. Kubalak S. Klewer S.E. McDonald J.A. J. Clin. Invest. 2000; 106: 349-360Crossref PubMed Scopus (729) Google Scholar). These results suggest that hyaluronan signals through Ras to regulate motility and are consistent with previous studies showing that exogenous hyaluronan-receptor interactions regulate Ras signaling (4Hall C.L. Wang C. Lange L.A. Turley E.A. J. Cell Biol. 1994; 126: 575-588Crossref PubMed Scopus (226) Google Scholar, 8Hall C.L. Yang B. Yang X. Zhang S. Turley M. Samuel S. Lange L.A. Wang C. Curpen G.D. Savani R.C. Greenberg A.H. Turley E.A. Cell. 1995; 82: 19-26Abstract Full Text PDF PubMed Scopus (269) Google Scholar). This ability of hyaluronan to activate intracellular signaling cascades requires interactions with cell-associated hyaluronan-binding proteins or hyaladherins (15Toole B.P. Curr. Opin. Cell Biol. 1990; 2: 839-844Crossref PubMed Scopus (403) Google Scholar) but is additionally modified by the amount and size of hyaluronan present in the environment of the cell. Further, not all cell types activate signaling cascades in response to hyaluronan (11Hall C.L. Collis L. Lange L. McNicol A. Gerrard J.M. Turley E.A. Matrix Biol. 2001; 20: 183-192Crossref PubMed Scopus (39) Google Scholar), indicating that cell background is also an important determinant. Here, we review current understanding of the mechanisms by which hyaluronan signals. The first cell-associated hyaladherin, RHAMM, whose cell surface form is now designated CD168, was isolated from embryonic heart cells (16Turley E.A. Biochem. Biophys. Res. Commun. 1982; 108: 1016-1024Crossref PubMed Scopus (93) Google Scholar). 2E. A. Turley and R. E. Harrison, www.glycoforum.gr.jp. Later CD44 was identified as the first integral hyaluronan “receptor.” Both RHAMM and CD44 mediate hyaluronan signaling and participate in growth factor-regulated signaling. However, they likely regulate signaling by different mechanisms because they are not homologous proteins, are compartmentalized differently in the cell (17Ponta H. Wainwright D. Herrlich P. Int. J. Biochem. Cell Biol. 1998; 30: 299-305Crossref PubMed Scopus (132) Google Scholar),2 and differ in the mechanisms by which they bind to hyaluronan (18Day A.J. Prestwich G.D. J. Biol. Chem. 2001; 277: 4585-4588Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar) (Figs.1 and 2). Additional cellular hyaladherins have been identified (19Banerji S., Ni, J. Wang S.X. Clasper S., Su, J. Tammi R. Jones M. Jackson D.G. J. Cell Biol. 1999; 144: 789-801Crossref PubMed Scopus (1335) Google Scholar, 20Grammatikakis N. Grammatikakis A. Yoneda M., Yu, Q. Banerjee S.D. Toole B.P. J. Biol. Chem. 1995; 270: 16198-16205Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 21Huang L. Grammatikakis N. Yoneda M. Banerjee S.D. Toole B.P. J. Biol. Chem. 2000; 275: 29829-29839Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 22Rao C.M. Deb T.B. Gupta S. Datta K. Biochim. Biophys. Acta. 1997; 1336: 387-393Crossref PubMed Scopus (29) Google Scholar), but their role in cell signaling has not yet been reported. Therefore, this review focuses upon the signaling cascades that RHAMM and CD44 regulate.Figure 2A current model for hyaluronan (HA)-dependent, RHAMM-mediated signaling pathways. RHAMM is an itinerant hyaladherin that occurs in multiple subcellular compartments and that can also be exported to the extracellular milieu where it binds to the cell surface. Cell surface RHAMM-hyaluronan interactions regulate signaling through Ras and Src. Cell surface RHAMM modifies the ability of the PDGF receptor to activate Erk kinase, a key map kinase involved in cell motility. Intracellular RHAMM proteins encode multiple kinase docking and recognition sites, and one intracellular form has been shown to physically associate with Erk1 kinase. Intracellular forms also associate with the cytoskeleton, notably interphase and mitotic spindle microtubules. The ability of intracellular RHAMM forms to associate with multiple signaling complexes and to associate with the cytoskeleton suggest that they function as adapter proteins like vinculin and paxillin. FAK, focal adhesion kinase.View Large Image Figure ViewerDownload (PPT) CD44 is an integral protein that is subject to extensive alternative splicing (23Lesley J. Hyman R. Kincade P. Adv. Immunol. 1993; 54: 271-335Crossref PubMed Scopus (1046) Google Scholar, 24Bourguignon L.Y.W. Curr. Top. Membr. 1996; 43: 293-312Crossref Scopus (24) Google Scholar, 25Bourguignon L.Y.W. Lokeshwar V.B., He, J. Chen X. Bourguignon G.J. Mol. Cell. Biol. 1992; 12: 4464-4471Crossref PubMed Scopus (81) Google Scholar, 26Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 12160-12164Crossref PubMed Scopus (996) Google Scholar). All CD44 isoforms contain a link module hyaluronan-binding site in their extracellular domain (see minireview by Day and Prestwich (18Day A.J. Prestwich G.D. J. Biol. Chem. 2001; 277: 4585-4588Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar) in this series). The binding of CD44 isoforms to hyaluronan affects cell adhesion to extracellular matrix components and is implicated in the stimulation of aggregation, proliferation, migration, and angiogenesis (23Lesley J. Hyman R. Kincade P. Adv. Immunol. 1993; 54: 271-335Crossref PubMed Scopus (1046) Google Scholar, 24Bourguignon L.Y.W. Curr. Top. Membr. 1996; 43: 293-312Crossref Scopus (24) Google Scholar, 25Bourguignon L.Y.W. Lokeshwar V.B., He, J. Chen X. Bourguignon G.J. Mol. Cell. Biol. 1992; 12: 4464-4471Crossref PubMed Scopus (81) Google Scholar, 27Bourguignon L.Y.W. Zhu D. Zhu H. Front. Biosci. 1998; 3: 637-649Crossref PubMed Scopus (111) Google Scholar, 28Lokeshwar V.B. Ida N. Bourguignon L.Y.W. J. Biol. Chem. 1996; 271: 23853-23864Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). The intracellular domain of CD44 isoforms selectively interacts with cytoskeletal proteins and regulates specific signaling (27Bourguignon L.Y.W. Zhu D. Zhu H. Front. Biosci. 1998; 3: 637-649Crossref PubMed Scopus (111) Google Scholar). Therefore, CD44 isoforms likely provide a direct association between hyaluronan and the cytoskeleton. The mechanisms by which CD44 achieves this association and the signaling cascades that it regulates are summarized in Fig. 1. CD44 is tightly coupled with at least two tyrosine kinases, p185HER2 (7Bourguignon L.Y.W. Zhu H.B. Chu A. Zhang L. Hung M.C. J. Biol. Chem. 1997; 272: 27913-27918Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) and c-Src kinase (6Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2001; 276: 7327-7333Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). CD44 and p185HER2 are physically linked to each other via interchain disulfide bonds; and hyaluronan can stimulate CD44-associated p185HER2 tyrosine kinase activity that leads to increased tumor cell growth (7Bourguignon L.Y.W. Zhu H.B. Chu A. Zhang L. Hung M.C. J. Biol. Chem. 1997; 272: 27913-27918Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). The cytoplasmic domain of CD44 binds to c-Src kinase at a single site with high affinity (6Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2001; 276: 7327-7333Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar,29Bourguignon L.Y.W. Zhu H. Shao L. Zhu D. Chen Y.W. Cell Motil. Cytoskeleton. 1999; 43: 269-287Crossref PubMed Scopus (147) Google Scholar). Importantly, hyaluronan interaction with CD44 stimulates c-Src kinase activity, increasing tyrosine phosphorylation of the cytoskeletal protein, cortactin. This attenuates the ability of cortactin to cross-link filamentous actin in vitro (Fig. 1) (6Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2001; 276: 7327-7333Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Most Src family kinases are modified with specific lipids that direct them to subdomains of the cell membrane called “rafts” that have high cholesterol and glycolipid content. The Src kinases, Lck and Fyn, associate with CD44 in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes (29Bourguignon L.Y.W. Zhu H. Shao L. Zhu D. Chen Y.W. Cell Motil. Cytoskeleton. 1999; 43: 269-287Crossref PubMed Scopus (147) Google Scholar). Thus, direct binding of CD44 to c-Src kinase in the membrane “rafts” may facilitate hyaluronan-mediated stimulation of the catalytic activity of c-Src kinase and induce cytoskeleton-regulated tumor cell migration. Therefore, the binding of hyaluronan to CD44 isoforms, which complex with p185HER2 and c-Src kinase, likely trigger direct “cross-talk” between two tyrosine kinase-linked signaling pathways during tumor progression. Rho GTPases such as RhoA and Rac1 participate in the interaction between CD44 and cytoskeletal proteins. In particular, RhoA is non-covalently linked to a CD44 alternate isoform (e.g.CD44V3,8–10) in breast tumor cells (30Oliferenko S. Kaverina I. Small J.V. Huber L.A. J. Cell Biol. 2000; 148: 1159-1164Crossref PubMed Scopus (144) Google Scholar). When complexed with CD44V3, RhoA stimulates Rho kinase (ROK) to phosphorylate several cellular proteins including CD44V3,8–10. This phosphorylation promotes binding of the CD44 variant to ankyrin (Fig. 1). Overexpression of the Rho-binding domain can act as a dominant negative inhibitor of ROK and reverse tumor cell-specific phenotypes (30Oliferenko S. Kaverina I. Small J.V. Huber L.A. J. Cell Biol. 2000; 148: 1159-1164Crossref PubMed Scopus (144) Google Scholar). Therefore, it has been proposed that CD44v3,8–10 and RhoA-mediated signaling are involved in the up-regulation of ROK and that this is necessary for membrane-cytoskeleton interactions and tumor cell migration during the progression of breast cancers (30Oliferenko S. Kaverina I. Small J.V. Huber L.A. J. Cell Biol. 2000; 148: 1159-1164Crossref PubMed Scopus (144) Google Scholar). Binding of hyaluronan to some CD44-expressing cells also activates Rac1 signaling, a pathway known to regulate actin assembly that is associated with membrane ruffling, cellular projections, cell motility, and cell transformation (31Bretscher A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 32Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2000; 275: 1829-1838Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). In particular, the cytoplasmic domain of CD44 binds to guanine nucleotide exchange factors such as Tiam1 and Vav2 that have been shown to catalyze the GDP-GTP exchange leading to hyaluronan-mediated tumor cell migration (Fig. 1) (32Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2000; 275: 1829-1838Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 33Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Cell Biol. 2000; 150: 177-191Crossref PubMed Scopus (118) Google Scholar, 34Bourguignon L.Y.W. Zhu H. Zhou B. Diedrich F. Singleton P.A. Hung M.-C. J. Biol. Chem. 2001; 277: 48679-48692Abstract Full Text Full Text PDF Scopus (168) Google Scholar). The fact that both Tiam1-Rac1 activation (31Bretscher A. Curr. Opin. Cell Biol. 1999; 11: 109-116Crossref PubMed Scopus (334) Google Scholar, 33Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Cell Biol. 2000; 150: 177-191Crossref PubMed Scopus (118) Google Scholar, 34Bourguignon L.Y.W. Zhu H. Zhou B. Diedrich F. Singleton P.A. Hung M.-C. J. Biol. Chem. 2001; 277: 48679-48692Abstract Full Text Full Text PDF Scopus (168) Google Scholar) and RhoA-mediated ROK activity (30Oliferenko S. Kaverina I. Small J.V. Huber L.A. J. Cell Biol. 2000; 148: 1159-1164Crossref PubMed Scopus (144) Google Scholar) are involved in regulating cytoskeleton function and cell motility in a hyaluronan- and CD44-dependent manner suggests these pathways play a pivotal role in hyaluronan-stimulated CD44 signaling. The first 19 residues of the cytoplasmic domain of CD44 interact with the cytoskeleton membrane linker proteins, ezrin/radixin/moesin (ERM) (32Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2000; 275: 1829-1838Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar), which contain the KKXn (K/R)K motif for phosphatidylinositol 4,5-bisphosphate (PIP2) binding (35Barret C. Roy C. Montcourrier P. Mangeat P. Niggli V. J. Cell Biol. 2000; 151: 1067-1079Crossref PubMed Scopus (204) Google Scholar). Mutation of this motif on ezrin results in the loss of the PIP2 requirement for optimal binding of ezrin to CD44 but does not influence the complex formation between ezrin and CD44 (35Barret C. Roy C. Montcourrier P. Mangeat P. Niggli V. J. Cell Biol. 2000; 151: 1067-1079Crossref PubMed Scopus (204) Google Scholar). These findings suggest that the linkage between ERM and CD44 can form in either a PIP2-dependent or a PIP2-independent manner. An involvement of PIP2in regulating CD44-ERM interaction during hyaluronan signaling has not yet been reported. Ankyrin is also a family of membrane-associated cytoskeletal proteins expressed in a variety of biological systems (24Bourguignon L.Y.W. Curr. Top. Membr. 1996; 43: 293-312Crossref Scopus (24) Google Scholar, 28Lokeshwar V.B. Ida N. Bourguignon L.Y.W. J. Biol. Chem. 1996; 271: 23853-23864Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). The cytoplasmic domain of CD44 (∼70 amino acids) is highly conserved in most of the CD44 isoforms and is directly involved in ankyrin binding (24Bourguignon L.Y.W. Curr. Top. Membr. 1996; 43: 293-312Crossref Scopus (24) Google Scholar, 28Lokeshwar V.B. Ida N. Bourguignon L.Y.W. J. Biol. Chem. 1996; 271: 23853-23864Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). Deletion mutation analyses indicate that at least two subregions within the CD44 cytoplasmic domain contribute to the ankyrin binding, namely region I (e.g. the high affinity ankyrin-binding region) and region II (e.g. the regulatory region). In particular, region I (306NGGNGTVEDRKPSEL320 in the mouse CD44 and 304NSGNGAVEDRKPSGL318 in the human CD44) is required for hyaluronan-mediated binding and cell adhesion (24Bourguignon L.Y.W. Curr. Top. Membr. 1996; 43: 293-312Crossref Scopus (24) Google Scholar). Furthermore, an ankyrin-binding domain of CD44 isoforms has also been shown to be necessary for oncogenic signaling and tumor cell transformation (27Bourguignon L.Y.W. Zhu D. Zhu H. Front. Biosci. 1998; 3: 637-649Crossref PubMed Scopus (111) Google Scholar). Recently, fragments of the ankyrin repeat domain and/or the subdomain 2 of ankyrin repeat domain have been identified as an ankyrin-binding region for both CD44 (26Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 12160-12164Crossref PubMed Scopus (996) Google Scholar) and Tiam1 (32Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Biol. Chem. 2000; 275: 1829-1838Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). Overexpression of these ankyrin fragments promotes hyaluronan-dependent and CD44-specific tumor cell migration (33Bourguignon L.Y.W. Zhu H. Shao L. Chen Y.W. J. Cell Biol. 2000; 150: 177-191Crossref PubMed Scopus (118) Google Scholar). These observations support the notion that CD44-ankyrin interaction is not only very important for presenting CD44 properly for hyaluronan binding but is also required for cytoskeleton activation during hyaluronan signaling (Fig. 1). Like CD44, RHAMM is alternatively spliced.2 Truncated RHAMM forms are also expressed in cells following injury (36Savani R.C. Wang C. Yang B. Zhang S. Kinsella M.G. Wight T.N. Stern R. Nance D.M. Turley E.A. J. Clin. Invest. 1995; 95: 1158-1168Crossref PubMed Scopus (176) Google Scholar), in tumors, and in some mutant active Ras-transformed cell lines (9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar,37Wang C. Thor A.D. Moore D.H., II Zhao Y. Kerschmann R. Stern R. Watson P.H. Turley E.A. Clin. Cancer Res. 1998; 4: 567-576PubMed Google Scholar, 38Ahrens T. Assmann V. Fieber C. Termeer C. Herrlich P. Hofmann M. Simon J.C. J. Invest. 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The RHAMM gene does not encode a traditional leader sequence to permit secretion via the traditional Golgi/endoplasmic reticulum export pathway, thus, resembling proteins such as bFGF, HIV Tat protein, the homeobox protein engrailed (44Prochiantz A. Curr. Opin. Cell Biol. 2000; 12: 400-406Crossref PubMed Scopus (273) Google Scholar), heat shock proteins (45Binder R.J. Han D.K. Srivastava P.K. Nat. Immunol. 2000; 1: 151-155Crossref PubMed Scopus (604) Google Scholar, 46Sondermann H. Becker T. Mayhew M. Wieland F. Hart Biol. Chem. 2000; PubMed Scopus Google Scholar), and Y. A. S. S. S. M.J. J. Cell Biol. 1998; PubMed Scopus Google Scholar). The binding of exogenous hyaluronan to cell surface RHAMM a key role in signaling as a for integral membrane proteins. the of intracellular RHAMM protein forms are not yet their ability to associate with kinases (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar, 9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar), (41Assmann V. Jenkinson D. Marshall J.F. Hart I.R. J. Cell Sci. 1999; 112: 3943-3954Crossref PubMed Google Scholar, B.D. Turley E.A. Nagy J.I. J. Neurosci. Res. 2001; 65: 6-16Crossref PubMed Scopus (32) Google Scholar), and the cytoskeleton (41Assmann V. Jenkinson D. Marshall J.F. Hart I.R. J. Cell Sci. 1999; 112: 3943-3954Crossref PubMed Google Scholar, 43Entwistle J. Hall C.L. Turley E.A. J. Cell. Biochem. 1996; 61: 569-577Crossref PubMed Scopus (439) Google Scholar) that they play key in cytoskeletal The of intracellular hyaladherins by RHAMM also the possibility that intracellular hyaluronan K. H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar, L. Hall C. Lange L. M. Prestwich R. Turley E.A. 1998; PubMed Scopus Google Scholar, Wight T.N. J. 1999; PubMed Scopus Google Scholar) a role in signaling. the of cell surface RHAMM from the intracellular RHAMM forms the potential for a association and the cell nucleus (Fig. 2). In this hyaladherins such as RHAMM contribute to the and of between the cell and the extracellular a that has been M.J. J. Cell. Biochem. 1998; Google Scholar). RHAMM a modified of signaling of S. D.A. J. Cell Sci. 2000; Scholar). Cell surface RHAMM-hyaluronan interactions mediate activation of the protein tyrosine kinases, Src (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar) and focal adhesion kinase (4Hall C.L. Wang C. Lange L.A. Turley E.A. J. Cell Biol. 1994; 126: 575-588Crossref PubMed Scopus (226) Google Scholar, 8Hall C.L. Yang B. Yang X. Zhang S. Turley M. Samuel S. Lange L.A. Wang C. Curpen G.D. Savani R.C. Greenberg A.H. Turley E.A. Cell. 1995; 82: 19-26Abstract Full Text PDF PubMed Scopus (269) Google Scholar, 10Lokeshwar V.B. Selzer M.G. J. Biol. Chem. 2000; 275: 27641-27649Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar), as as Erk kinases V.B. Selzer M.G. J. Biol. Chem. 2000; 275: 27641-27649Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar) and protein kinase C (11Hall C.L. Collis L. Lange L. McNicol A. Gerrard J.M. Turley E.A. Matrix Biol. 2001; 20: 183-192Crossref PubMed Scopus (39) Google Scholar, 12Slevin M. Krupinski J. Kumar S. Gaffney J. Lab. Invest. 1998; 78: 987-1003PubMed Google Scholar). cell surface RHAMM is required for activation of Erk kinases through PDGF (9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar), growth factor Li, X. P.A. Nagy J.I. Neurosci. 2001; PubMed Scopus Google Scholar), and injury B.D. L. J. 1999; PubMed Scopus Google Scholar). of Src through cell surface RHAMM is (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar) but is required for of focal and for cell motility (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar). that are on tyrosine as a of interactions include focal adhesion kinase, and the MAP kinases, Erk1 and V.B. Selzer M.G. J. Biol. Chem. 2000; 275: 27641-27649Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). RHAMM with of cellular Erk1 kinase (9Zhang S. Chang M.C. Zylka D. Turley S. Harrison R. Turley E.A. J. Biol. Chem. 1998; 273: 11342-11348Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar) and of cellular Src (5Hall C.L. Lange L.A. Prober D.A. Zhang S. Turley E.A. Oncogene. 1996; 13: 2213-2224PubMed Google Scholar), as by RHAMM recognition for both Src and Erk it is likely that intracellular RHAMM forms associate directly with these kinases. RHAMM multiple and as as for serine/threonine kinases. 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