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Departments of
*
Biochemistry and
Orthopedic Surgery, Section of Biochemistry and Molecular Biology, Rush University at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612; and
Immunex Corporation, Seattle, WA 98101
CD44 is a widely expressed integral membrane glycoprotein that
serves as a specific adhesion receptor for the extracellular matrix
glycosaminoglycan hyaluronan. CD44 participates in a variety of
physiological and pathological processes through its role in cell
adhesion. Under appropriate conditions, the ectodomain of CD44 is
proteolytically removed from the cell surface. In this study we show
that excessive CD44 shedding can be induced in mouse fibroblasts and
monocytes upon exposure of these cells to a CD44-specific Ab
immobilized on plastic, whereas treatment with phorbol ester induces
significantly enhanced CD44 release from the monocytes only. CD44
shedding proceeds normally in fibroblasts and monocytes deficient in
TNF-
converting enzyme (TACE), a sheddase involved in the processing
of several substrates. Conversely, activation of the CD44 protease has
no effect on the release of TNF- from TACE-expressing cells,
although the same metalloprotease inhibitor effectively blocks both
TACE and the CD44 sheddase. Concomitant with anti-CD44 Ab- or
phorbol ester-induced CD44 shedding, dramatic changes are observed in
cell morphology and the structure of the actin cytoskeleton. Disruption
of actin assembly with cytochalasin reduces CD44 shedding, but not the
release of TNF-. Moreover, pharmacological activation of Rho family
GTPases Rac1 and Cdc42, which regulate actin filament assembly into
distinct cytoskeletal structures, has a profound effect on CD44
release. We conclude that the CD44 sheddase and TACE are distinct
enzymes, and that Ab- and phorbol ester-enhanced cleavage of CD44 is
controlled in a cell type-dependent fashion by Rho GTPases through the
cytoskeleton.
This article has been cited by other articles:
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K. J. Garton, P. J. Gough, and E. W. Raines Emerging roles for ectodomain shedding in the regulation of inflammatory responses J. Leukoc. Biol., June 1, 2006; 79(6): 1105 - 1116. [Abstract] [Full Text] [PDF]
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K. N. Sugahara, T. Hirata, H. Hayasaka, R. Stern, T. Murai, and M. Miyasaka Tumor Cells Enhance Their Own CD44 Cleavage and Motility by Generating Hyaluronan Fragments J. Biol. Chem., March 3, 2006; 281(9): 5861 - 5868. [Abstract] [Full Text] [PDF]
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 S. S. Bohlson, R. Silva, M. I. Fonseca, and A. J. Tenner CD93 Is Rapidly Shed from the Surface of Human Myeloid Cells and the Soluble Form Is Detected in Human Plasma J. Immunol., July 15, 2005; 175(2): 1239 - 1247. [Abstract] [Full Text] [PDF]
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 R. J. McKallip, M. Fisher, U. Gunthert, A. K. Szakal, P. S. Nagarkatti, and M. Nagarkatti Role of CD44 and Its v7 Isoform in Staphylococcal Enterotoxin B-Induced Toxic Shock: CD44 Deficiency on Hepatic Mononuclear Cells Leads to Reduced Activation-Induced Apoptosis That Results in Increased Liver Damage Infect. Immun., January 1, 2005; 73(1): 50 - 61. [Abstract] [Full Text] [PDF]
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S. Szanto, I. Gal, A. Gonda, T. T. Glant, and K. Mikecz Expression of L-Selectin, but Not CD44, Is Required for Early Neutrophil Extravasation in Antigen-Induced Arthritis J. Immunol., June 1, 2004; 172(11): 6723 - 6734. [Abstract] [Full Text] [PDF]
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T. Murai, Y. Miyazaki, H. Nishinakamura, K. N. Sugahara, T. Miyauchi, Y. Sako, T. Yanagida, and M. Miyasaka Engagement of CD44 Promotes Rac Activation and CD44 Cleavage during Tumor Cell Migration J. Biol. Chem., February 6, 2004; 279(6): 4541 - 4550. [Abstract] [Full Text] [PDF]
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 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]
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P. W. Park, T. J. Foster, E. Nishi, S. J. Duncan, M. Klagsbrun, and Y. Chen Activation of Syndecan-1 Ectodomain Shedding by Staphylococcus aureus {alpha}-Toxin and {beta}-Toxin J. Biol. Chem., January 2, 2004; 279(1): 251 - 258. [Abstract] [Full Text] [PDF]
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K. N. Sugahara, T. Murai, H. Nishinakamura, H. Kawashima, H. Saya, and M. Miyasaka Hyaluronan Oligosaccharides Induce CD44 Cleavage and Promote Cell Migration in CD44-expressing Tumor Cells J. Biol. Chem., August 22, 2003; 278(34): 32259 - 32265. [Abstract] [Full Text] [PDF]
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 J. Cichy and E. Pure The liberation of CD44 J. Cell Biol., June 9, 2003; 161(5): 839 - 843. [Abstract] [Full Text] [PDF]
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D. HUDRISIER and P. BONGRAND Intercellular transfer of antigen-presenting cell determinants onto T cells: molecular mechanisms and biological significance FASEB J, April 1, 2002; 16(6): 477 - 486. [Abstract] [Full Text] [PDF]
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 T. L. Davis, F. Buerger, and A. E. Cress Differential Regulation of a Novel Variant of the {alpha}6 Integrin, {alpha}6p Cell Growth Differ., March 1, 2002; 13(3): 107 - 113. [Abstract] [Full Text] [PDF]
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