Evidence from a large body of studies indicates that CD44 is involved in a number of important biological processes, including lymphocyte activation and homing, hematopoiesis, and tumor progression and metastasis. A proper understanding of the role of CD44 in these processes has been severely hampered by a lack of insight into the mode in which CD44 communicates with intracellular signal transduction pathways. In this report, we have addressed this aspect of CD44 functioning by studying CD44 signaling in T lymphocytes. We show that ligation of CD44 by monoclonal antibodies (mAbs) transduces signals to T cells which lead to tyrosine phosphorylation of ZAP-70 and other intracellular proteins. In vitro kinase assays demonstrate that cross-linking of CD44 induces an increase in the intrinsic activity of p56. Furthermore, immunoprecipitations show that CD44 is physically associated with p56. Our findings suggest that tyrosine kinases, particularly p56, play a central role in CD44 mediated signaling.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				G. Hutas, E. Bajnok, I. Gal, A. Finnegan, T. T. Glant, and K. Mikecz CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis Blood, December 15, 2008; 112(13): 4999 - 5006. [Abstract] [Full Text] [PDF]

				N. K. Y. Wong, J. C. Y. Lai, D. Birkenhead, A. S. Shaw, and P. Johnson CD45 Down-Regulates Lck-Mediated CD44 Signaling and Modulates Actin Rearrangement in T Cells J. Immunol., November 15, 2008; 181(10): 7033 - 7043. [Abstract] [Full Text] [PDF]

				J.-L. Lee, M.-J. Wang, P.-R. Sudhir, and J.-Y. Chen CD44 Engagement Promotes Matrix-Derived Survival through the CD44-SRC-Integrin Axis in Lipid Rafts Mol. Cell. Biol., September 15, 2008; 28(18): 5710 - 5723. [Abstract] [Full Text] [PDF]

				J. Zeilstra, S. P.J. Joosten, M. Dokter, E. Verwiel, M. Spaargaren, and S. T. Pals Deletion of the WNT Target and Cancer Stem Cell Marker CD44 in Apc(Min/+) Mice Attenuates Intestinal Tumorigenesis Cancer Res., May 15, 2008; 68(10): 3655 - 3661. [Abstract] [Full Text] [PDF]

				M. S. Hossain, J. D. Roback, B. P. Pollack, D. L. Jaye, A. Langston, and E. K. Waller Chronic GvHD decreases antiviral immune responses in allogeneic BMT Blood, May 15, 2007; 109(10): 4548 - 4556. [Abstract] [Full Text] [PDF]

				R. F. Thorne, J. W. Legg, and C. M. Isacke The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events J. Cell Sci., January 22, 2004; 117(3): 373 - 380. [Abstract] [Full Text] [PDF]

				B. Roscic-Mrkic, M. Fischer, C. Leemann, A. Manrique, C. J. Gordon, J. P. Moore, A. E. I. Proudfoot, and A. Trkola RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement Blood, August 15, 2003; 102(4): 1169 - 1177. [Abstract] [Full Text] [PDF]

				T. Katakai, T. Hara, M. Sugai, H. Gonda, Y. Nambu, E. Matsuda, Y. Agata, and A. Shimizu Chemokine-independent Preference for T-helper-1 Cells in Transendothelial Migration J. Biol. Chem., December 20, 2002; 277(52): 50948 - 50958. [Abstract] [Full Text] [PDF]

				B. Seddon and R. Zamoyska TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells J. Immunol., September 15, 2002; 169(6): 2997 - 3005. [Abstract] [Full Text] [PDF]

				S. Khaldoyanidi, S. Karakhanova, J. Sleeman, P. Herrlich, and H. Ponta CD44 variant-specific antibodies trigger hemopoiesis by selective release of cytokines from bone marrow macrophages Blood, May 13, 2002; 99(11): 3955 - 3961. [Abstract] [Full Text] [PDF]

				M. Suzuki, H. Kobayashi, M. Fujie, T. Nishida, M. Takigawa, N. Kanayama, and T. Terao Kunitz-type Protease Inhibitor Bikunin Disrupts Phorbol Ester-induced Oligomerization of CD44 Variant Isoforms Containing Epitope v9 and Subsequently Suppresses Expression of Urokinase-type Plasminogen Activator in Human Chondrosarcoma Cells J. Biol. Chem., March 1, 2002; 277(10): 8022 - 8032. [Abstract] [Full Text] [PDF]

				O. Christ, U. Gunthert, D.-S. Schmidt, and M. Zoller Allogeneic reconstitution after nonmyeloablative conditioning: mitigation of graft-versus-host and host-versus-graft reactivity by anti-CD44v6 J. Leukoc. Biol., January 1, 2002; 71(1): 33 - 46. [Abstract] [Full Text] [PDF]

				R.-S. Charrad, Z. Gadhoum, J. Qi, A. Glachant, M. Allouche, C. Jasmin, C. Chomienne, and F. Smadja-Joffe Effects of anti-CD44 monoclonal antibodies on differentiation and apoptosis of human myeloid leukemia cell lines Blood, January 1, 2002; 99(1): 290 - 299. [Abstract] [Full Text] [PDF]

				A P Cairns, A D Crockard, J R McConnell, P A Courtney, and A L Bell Reduced expression of CD44 on monocytes and neutrophils in systemic lupus erythematosus: relations with apoptotic neutrophils and disease activity Ann Rheum Dis, October 1, 2001; 60(10): 950 - 955. [Abstract] [Full Text] [PDF]

				R. C. Bates, N. S. Edwards, G. F. Burns, and D. E. Fisher A CD44 Survival Pathway Triggers Chemoresistance via Lyn Kinase and Phosphoinositide 3-Kinase/Akt in Colon Carcinoma Cells Cancer Res., July 1, 2001; 61(13): 5275 - 5283. [Abstract] [Full Text] [PDF]

				G. Sconocchia, L. Campagnano, D. Adorno, A. Iacona, N. Y. Cococcetta, V. Boffo, S. Amadori, and C. U. Casciani CD44 ligation on peripheral blood polymorphonuclear cells induces interleukin-6 production Blood, June 1, 2001; 97(11): 3621 - 3627. [Abstract] [Full Text] [PDF]

				S. L. Blass, E. Pure, and C. A. Hunter A Role for CD44 in the Production of IFN-{{gamma}} and Immunopathology During Infection with Toxoplasma gondii J. Immunol., May 1, 2001; 166(9): 5726 - 5732. [Abstract] [Full Text] [PDF]

				H. Wang, Y. Zhan, L. Xu, G. Z. Feuerstein, and X. Wang Use of Suppression Subtractive Hybridization for Differential Gene Expression in Stroke : Discovery of CD44 Gene Expression and Localization in Permanent Focal Stroke in Rats Stroke, April 1, 2001; 32(4): 1020 - 1027. [Abstract] [Full Text] [PDF]

				T. Fujimoto, H. Kawashima, T. Tanaka, M. Hirose, N. Toyama-Sorimachi, Y. Matsuzawa, and M. Miyasaka CD44 binds a chondroitin sulfate proteoglycan, aggrecan Int. Immunol., March 1, 2001; 13(3): 359 - 366. [Abstract] [Full Text] [PDF]

				S. B. Wallach-Dayan, V. Grabovsky, J. Moll, J. Sleeman, P. Herrlich, R. Alon, and D. Naor CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes J. Cell Sci., January 10, 2001; 114(19): 3463 - 3477. [Abstract] [Full Text] [PDF]

				N Foger, R Marhaba, and M Zoller Involvement of CD44 in cytoskeleton rearrangement and raft reorganization in T cells J. Cell Sci., January 3, 2001; 114(6): 1169 - 1178. [Abstract] [PDF]

				V. J. M. Wielenga, R. van der Voort, T. E. I. Taher, L. Smit, E. A. Beuling, C. van Krimpen, M. Spaargaren, and S. T. Pals Expression of c-Met and Heparan-Sulfate Proteoglycan Forms of CD44 in Colorectal Cancer Am. J. Pathol., November 1, 2000; 157(5): 1563 - 1573. [Abstract] [Full Text] [PDF]

				M. Allouche, R. S. Charrad, A. Bettaieb, C. Greenland, C. Grignon, and F. Smadja-Joffe Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells Blood, August 1, 2000; 96(3): 1187 - 1190. [Abstract] [Full Text] [PDF]

				S. Bruno, M. Fabbi, M. Tiso, B. Santamaria, F. Ghiotto, D. Saverino, C. Tenca, D. Zarcone, S. Ferrini, E. Ciccone, et al. Cell activation via CD44 occurs in advanced stages of squamous cell carcinogenesis Carcinogenesis, May 1, 2000; 21(5): 893 - 900. [Abstract] [Full Text] [PDF]

				P. Drillenburg and S. T. Pals Cell adhesion receptors in lymphoma dissemination Blood, March 15, 2000; 95(6): 1900 - 1910. [Abstract] [Full Text] [PDF]

				J. D. Alvarez, D. H. Yasui, H. Niida, T. Joh, D. Y. Loh, and T. Kohwi-Shigematsu The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development Genes & Dev., March 1, 2000; 14(5): 521 - 535. [Abstract] [Full Text]

				Y. B. Choi, C. K. Kim, and Y. Yun Lad, an Adapter Protein Interacting with the SH2 Domain of p56lck, Is Required for T Cell Activation ,2 J. Immunol., November 15, 1999; 163(10): 5242 - 5249. [Abstract] [Full Text] [PDF]

				U. Dianzani, M. Bragardo, A. Tosti, L. Ruggeri, I. Volpi, M. Casucci, F. Bottarel, M. J. Feito, S. Bonissoni, and A. Velardi CD44 signaling through p56lck involves lateral association with CD4 in human CD4+ T cells Int. Immunol., July 1, 1999; 11(7): 1085 - 1092. [Abstract] [Full Text] [PDF]

				S. P. Evanko, J. C. Angello, and T. N. Wight Formation of Hyaluronan- and Versican-Rich Pericellular Matrix Is Required for Proliferation and Migration of Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 1004 - 1013. [Abstract] [Full Text] [PDF]

				R. van der Voort, T. E. I. Taher, V. J. M. Wielenga, M. Spaargaren, R. Prevo, L. Smit, G. David, G. Hartmann, E. Gherardi, and S. T. Pals Heparan Sulfate-modified CD44 Promotes Hepatocyte Growth Factor/Scatter Factor-induced Signal Transduction through the Receptor Tyrosine Kinase c-Met J. Biol. Chem., March 5, 1999; 274(10): 6499 - 6506. [Abstract] [Full Text] [PDF]

				H. Haegel-Kronenberger, H. de la Salle, A. Bohbot, F. Oberling, J.-P. Cazenave, and D. Hanau Adhesive and/or Signaling Functions of CD44 Isoforms in Human Dendritic Cells J. Immunol., October 15, 1998; 161(8): 3902 - 3911. [Abstract] [Full Text] [PDF]

				B. Wittig, C. Schwarzler, N. Fohr, U. Gunthert, and M. Zoller Cutting Edge: Curative Treatment of an Experimentally Induced Colitis by a CD44 Variant V7-Specific Antibody J. Immunol., August 1, 1998; 161(3): 1069 - 1073. [Abstract] [Full Text] [PDF]

				Y. Yakushijin, J. Steckel, S. Kharbanda, R. Hasserjian, D. Neuberg, W.-m. Jiang, I. Anderson, and M. A. Shipp A Directly Spliced Exon 10-Containing CD44 Variant Promotes the Metastasis and Homotypic Aggregation of Aggressive Non-Hodgkin's Lymphoma Blood, June 1, 1998; 91(11): 4282 - 4291. [Abstract] [Full Text] [PDF]

				S. Ilangumaran, A. Briol, and D. C. Hoessli CD44 Selectively Associates With Active Src Family Protein Tyrosine Kinases Lck and Fyn in Glycosphingolipid-Rich Plasma Membrane Domains of Human Peripheral Blood Lymphocytes Blood, May 15, 1998; 91(10): 3901 - 3908. [Abstract] [Full Text] [PDF]

				C. Claas, S. Seiter, A. Claas, L. Savelyeva, M. Schwab, and M. Zoller Association Between the Rat Homologue of CO-029, a Metastasis-associated Tetraspanin Molecule and Consumption Coagulopathy J. Cell Biol., April 6, 1998; 141(1): 267 - 280. [Abstract] [Full Text] [PDF]

				J. P. Sleeman, K. Kondo, J. Moll, H. Ponta, and P. Herrlich Variant Exons v6 and v7 Together Expand the Repertoire of Glycosaminoglycans Bound by CD44 J. Biol. Chem., December 12, 1997; 272(50): 31837 - 31844. [Abstract] [Full Text] [PDF]

				T. Hanada, L. Lin, K. G. Chandy, S. S. Oh, and A. H. Chishti Human Homologue of the Drosophila Discs Large Tumor Suppressor Binds to p56lck Tyrosine Kinase and Shaker Type Kv1.3 Potassium Channel in T Lymphocytes J. Biol. Chem., October 24, 1997; 272(43): 26899 - 26904. [Abstract] [Full Text] [PDF]

				A. W. Griffioen, M. J.H. Coenen, C. A. Damen, S. M.M. Hellwig, D. H.J. van Weering, W. Vooys, G. H. Blijham, and G. Groenewegen CD44 Is Involved in Tumor Angiogenesis; an Activation Antigen on Human Endothelial Cells Blood, August 1, 1997; 90(3): 1150 - 1159. [Abstract] [Full Text] [PDF]

				G. Sconocchia, J. A. Titus, and D. M. Segal Signaling Pathways Regulating CD44-Dependent Cytolysis in Natural Killer Cells Blood, July 15, 1997; 90(2): 716 - 725. [Abstract] [Full Text] [PDF]

				R. v. d. Voort, T. E.I. Taher, R. M.J. Keehnen, L. Smit, M. Groenink, and S. T. Pals Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met-Hepatocyte Growth Factor/Scatter Factor Pathway J. Exp. Med., June 16, 1997; 185(12): 2121 - 2131. [Abstract] [Full Text] [PDF]

				L. Y. W. Bourguignon, H. Zhu, L. Shao, and Y.-W. Chen CD44 Interaction with c-Src Kinase Promotes Cortactin-mediated Cytoskeleton Function and Hyaluronic Acid-dependent Ovarian Tumor Cell Migration J. Biol. Chem., March 2, 2001; 276(10): 7327 - 7336. [Abstract] [Full Text] [PDF]

				R. Li, N. Wong, M. D. Jabali, and P. Johnson CD44-initiated Cell Spreading Induces Pyk2 Phosphorylation, Is Mediated by Src Family Kinases, and Is Negatively Regulated by CD45 J. Biol. Chem., July 27, 2001; 276(31): 28767 - 28773. [Abstract] [Full Text] [PDF]