Skip to main content
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1992 Aug 2;118(4):971–977. doi: 10.1083/jcb.118.4.971

CD44H regulates tumor cell migration on hyaluronate-coated substrate

PMCID: PMC2289565  PMID: 1380003

Abstract

CD44 is a broadly distributed cell surface glycoprotein expressed in different isoforms in various tissues and cell lines. One of two recently characterized human isoforms, CD44H, is a cell surface receptor for hyaluronate, suggesting a role in the regulation of cell- cell and cell-substrate interactions as well as of cell migration. While CD44H has been shown to mediate cell adhesion, direct demonstration that CD44H expression promotes cell motility has been lacking. In this work we show that a human melanoma cell line, stably transfected with CD44H, displays enhanced motility on hyaluronate- coated surfaces while transfectants expressing an isoform that does not bind hyaluronate, CD44E, fail to do so. Migration of CD44H-expressing transfectants is observed to be blocked by a soluble CD44- immunoglobulin fusion protein as well as by anti-CD44 antibody, and to depend on the presence of the cytoplasmic domain of CD44. However, cells expressing CD44H cytoplasmic deletion mutants retain significant binding capacity to hyaluronate-coated substrate. Taken together, our results provide direct evidence that CD44H plays a major role in regulating cell migration on hyaluronate-coated substrate.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aruffo A., Kolanus W., Walz G., Fredman P., Seed B. CD62/P-selectin recognition of myeloid and tumor cell sulfatides. Cell. 1991 Oct 4;67(1):35–44. doi: 10.1016/0092-8674(91)90570-o. [DOI] [PubMed] [Google Scholar]
  2. Aruffo A., Stamenkovic I., Melnick M., Underhill C. B., Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. doi: 10.1016/0092-8674(90)90694-a. [DOI] [PubMed] [Google Scholar]
  3. Brown T. A., Bouchard T., St John T., Wayner E., Carter W. G. Human keratinocytes express a new CD44 core protein (CD44E) as a heparan-sulfate intrinsic membrane proteoglycan with additional exons. J Cell Biol. 1991 Apr;113(1):207–221. doi: 10.1083/jcb.113.1.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Byers H. R., Etoh T., Doherty J. R., Sober A. J., Mihm M. C., Jr Cell migration and actin organization in cultured human primary, recurrent cutaneous and metastatic melanoma. Time-lapse and image analysis. Am J Pathol. 1991 Aug;139(2):423–435. [PMC free article] [PubMed] [Google Scholar]
  5. Camp R. L., Kraus T. A., Puré E. Variations in the cytoskeletal interaction and posttranslational modification of the CD44 homing receptor in macrophages. J Cell Biol. 1991 Dec;115(5):1283–1292. doi: 10.1083/jcb.115.5.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Culty M., Miyake K., Kincade P. W., Sikorski E., Butcher E. C., Underhill C., Silorski E. The hyaluronate receptor is a member of the CD44 (H-CAM) family of cell surface glycoproteins. J Cell Biol. 1990 Dec;111(6 Pt 1):2765–2774. doi: 10.1083/jcb.111.6.2765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Denning S. M., Le P. T., Singer K. H., Haynes B. F. Antibodies against the CD44 p80, lymphocyte homing receptor molecule augment human peripheral blood T cell activation. J Immunol. 1990 Jan 1;144(1):7–15. [PubMed] [Google Scholar]
  8. Goodman S. L., Risse G., von der Mark K. The E8 subfragment of laminin promotes locomotion of myoblasts over extracellular matrix. J Cell Biol. 1989 Aug;109(2):799–809. doi: 10.1083/jcb.109.2.799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Günthert U., Hofmann M., Rudy W., Reber S., Zöller M., Haussmann I., Matzku S., Wenzel A., Ponta H., Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991 Apr 5;65(1):13–24. doi: 10.1016/0092-8674(91)90403-l. [DOI] [PubMed] [Google Scholar]
  10. Hart I. R., Birch M., Marshall J. F. Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Rev. 1991 Jun;10(2):115–128. doi: 10.1007/BF00049409. [DOI] [PubMed] [Google Scholar]
  11. Hofmann M., Rudy W., Zöller M., Tölg C., Ponta H., Herrlich P., Günthert U. CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res. 1991 Oct 1;51(19):5292–5297. [PubMed] [Google Scholar]
  12. Horst E., Meijer C. J., Radaszkiewicz T., Ossekoppele G. J., Van Krieken J. H., Pals S. T. Adhesion molecules in the prognosis of diffuse large-cell lymphoma: expression of a lymphocyte homing receptor (CD44), LFA-1 (CD11a/18), and ICAM-1 (CD54). Leukemia. 1990 Aug;4(8):595–599. [PubMed] [Google Scholar]
  13. Hällgren R., Gerdin B., Tufveson G. Hyaluronic acid accumulation and redistribution in rejecting rat kidney graft. Relationship to the transplantation edema. J Exp Med. 1990 Jun 1;171(6):2063–2076. doi: 10.1084/jem.171.6.2063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jacobson K., O'Dell D., August J. T. Lateral diffusion of an 80,000-dalton glycoprotein in the plasma membrane of murine fibroblasts: relationships to cell structure and function. J Cell Biol. 1984 Nov;99(5):1624–1633. doi: 10.1083/jcb.99.5.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jacobson K., O'Dell D., Holifield B., Murphy T. L., August J. T. Redistribution of a major cell surface glycoprotein during cell movement. J Cell Biol. 1984 Nov;99(5):1613–1623. doi: 10.1083/jcb.99.5.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jalkanen S., Bargatze R. F., de los Toyos J., Butcher E. C. Lymphocyte recognition of high endothelium: antibodies to distinct epitopes of an 85-95-kD glycoprotein antigen differentially inhibit lymphocyte binding to lymph node, mucosal, or synovial endothelial cells. J Cell Biol. 1987 Aug;105(2):983–990. doi: 10.1083/jcb.105.2.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jalkanen S., Reichert R. A., Gallatin W. M., Bargatze R. F., Weissman I. L., Butcher E. C. Homing receptors and the control of lymphocyte migration. Immunol Rev. 1986 Jun;91:39–60. doi: 10.1111/j.1600-065x.1986.tb01483.x. [DOI] [PubMed] [Google Scholar]
  18. Kalomiris E. L., Bourguignon L. Y. Lymphoma protein kinase C is associated with the transmembrane glycoprotein, GP85, and may function in GP85-ankyrin binding. J Biol Chem. 1989 May 15;264(14):8113–8119. [PubMed] [Google Scholar]
  19. Knudson C. B., Knudson W. Similar epithelial-stromal interactions in the regulation of hyaluronate production during limb morphogenesis and tumor invasion. Cancer Lett. 1990 Jul 16;52(2):113–122. doi: 10.1016/0304-3835(90)90253-t. [DOI] [PubMed] [Google Scholar]
  20. Knudson W., Biswas C., Li X. Q., Nemec R. E., Toole B. P. The role and regulation of tumour-associated hyaluronan. Ciba Found Symp. 1989;143:150-9; discussion 159-69, 281-5. doi: 10.1002/9780470513774.ch10. [DOI] [PubMed] [Google Scholar]
  21. Knudson W., Biswas C., Toole B. P. Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6767–6771. doi: 10.1073/pnas.81.21.6767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lacy B. E., Underhill C. B. The hyaluronate receptor is associated with actin filaments. J Cell Biol. 1987 Sep;105(3):1395–1404. doi: 10.1083/jcb.105.3.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lesley J., He Q., Miyake K., Hamann A., Hyman R., Kincade P. W. Requirements for hyaluronic acid binding by CD44: a role for the cytoplasmic domain and activation by antibody. J Exp Med. 1992 Jan 1;175(1):257–266. doi: 10.1084/jem.175.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lesley J., Schulte R., Hyman R. Binding of hyaluronic acid to lymphoid cell lines is inhibited by monoclonal antibodies against Pgp-1. Exp Cell Res. 1990 Apr;187(2):224–233. doi: 10.1016/0014-4827(90)90085-o. [DOI] [PubMed] [Google Scholar]
  25. Lindahl U., Hök M. Glycosaminoglycans and their binding to biological macromolecules. Annu Rev Biochem. 1978;47:385–417. doi: 10.1146/annurev.bi.47.070178.002125. [DOI] [PubMed] [Google Scholar]
  26. Miyake K., Underhill C. B., Lesley J., Kincade P. W. Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition. J Exp Med. 1990 Jul 1;172(1):69–75. doi: 10.1084/jem.172.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Quackenbush E. J., Vera S., Greaves A., Letarte M. Confirmation by peptide sequence and co-expression on various cell types of the identity of CD44 and P85 glycoprotein. Mol Immunol. 1990 Oct;27(10):947–955. doi: 10.1016/0161-5890(90)90117-i. [DOI] [PubMed] [Google Scholar]
  28. Ruoslahti E. Proteoglycans in cell regulation. J Biol Chem. 1989 Aug 15;264(23):13369–13372. [PubMed] [Google Scholar]
  29. Ruoslahti E., Yamaguchi Y. Proteoglycans as modulators of growth factor activities. Cell. 1991 Mar 8;64(5):867–869. doi: 10.1016/0092-8674(91)90308-l. [DOI] [PubMed] [Google Scholar]
  30. Seed B. An LFA-3 cDNA encodes a phospholipid-linked membrane protein homologous to its receptor CD2. 1987 Oct 29-Nov 4Nature. 329(6142):840–842. doi: 10.1038/329840a0. [DOI] [PubMed] [Google Scholar]
  31. Shimizu Y., Van Seventer G. A., Siraganian R., Wahl L., Shaw S. Dual role of the CD44 molecule in T cell adhesion and activation. J Immunol. 1989 Oct 15;143(8):2457–2463. [PubMed] [Google Scholar]
  32. St John T., Meyer J., Idzerda R., Gallatin W. M. Expression of CD44 confers a new adhesive phenotype on transfected cells. Cell. 1990 Jan 12;60(1):45–52. doi: 10.1016/0092-8674(90)90714-p. [DOI] [PubMed] [Google Scholar]
  33. Stamenkovic I., Amiot M., Pesando J. M., Seed B. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell. 1989 Mar 24;56(6):1057–1062. doi: 10.1016/0092-8674(89)90638-7. [DOI] [PubMed] [Google Scholar]
  34. Stamenkovic I., Aruffo A., Amiot M., Seed B. The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate-bearing cells. EMBO J. 1991 Feb;10(2):343–348. doi: 10.1002/j.1460-2075.1991.tb07955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sy M. S., Guo Y. J., Stamenkovic I. Distinct effects of two CD44 isoforms on tumor growth in vivo. J Exp Med. 1991 Oct 1;174(4):859–866. doi: 10.1084/jem.174.4.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tarone G., Ferracini R., Galetto G., Comoglio P. A cell surface integral membrane glycoprotein of 85,000 mol wt (gp85) associated with triton X-100-insoluble cell skeleton. J Cell Biol. 1984 Aug;99(2):512–519. doi: 10.1083/jcb.99.2.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Toole B. P., Biswas C., Gross J. Hyaluronate and invasiveness of the rabbit V2 carcinoma. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6299–6303. doi: 10.1073/pnas.76.12.6299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Turley E. A., Austen L., Vandeligt K., Clary C. Hyaluronan and a cell-associated hyaluronan binding protein regulate the locomotion of ras-transformed cells. J Cell Biol. 1991 Mar;112(5):1041–1047. doi: 10.1083/jcb.112.5.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Turley E. A., Tretiak M. Glycosaminoglycan production by murine melanoma variants in vivo and in vitro. Cancer Res. 1985 Oct;45(10):5098–5105. [PubMed] [Google Scholar]
  40. Watson S. R., Imai Y., Fennie C., Geoffroy J. S., Rosen S. D., Lasky L. A. A homing receptor-IgG chimera as a probe for adhesive ligands of lymph node high endothelial venules. J Cell Biol. 1990 Jun;110(6):2221–2229. doi: 10.1083/jcb.110.6.2221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Webb D. S., Shimizu Y., Van Seventer G. A., Shaw S., Gerrard T. L. LFA-3, CD44, and CD45: physiologic triggers of human monocyte TNF and IL-1 release. Science. 1990 Sep 14;249(4974):1295–1297. doi: 10.1126/science.1697984. [DOI] [PubMed] [Google Scholar]
  42. Weigel P. H., Frost S. J., LeBoeuf R. D., McGary C. T. The specific interaction between fibrin(ogen) and hyaluronan: possible consequences in haemostasis, inflammation and wound healing. Ciba Found Symp. 1989;143:248-61; discussion 261-4, 281-5. doi: 10.1002/9780470513774.ch15. [DOI] [PubMed] [Google Scholar]
  43. West D. C., Kumar S. Hyaluronan and angiogenesis. Ciba Found Symp. 1989;143:187-201; discussion 201-7, 281-5. doi: 10.1002/9780470513774.ch12. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES