Proteinase-mediated Release of Epithelial Cell-associated CD44

Abstract

CD44 is a receptor for the matrix glycosaminoglycan hyaluronan. Proteoglycan forms of CD44 also exhibit affinity for fibronectin and collagen as well as chemokines and growth factors. CD44 plays a role in autoimmunity, inflammation, and tumor progression. Soluble CD44 (sCD44) is found in plasma, and the levels of sCD44 correlate with immune function and some malignancies. The mechanisms by which sCD44 is generated and its function are unknown. We demonstrate here that normal bronchial epithelial cells spontaneously release sCD44. Exposure to phagocyte-and bacterium-derived proteinases markedly increased the release of sCD44 from epithelial cells. The spontaneously released sCD44 was incorporated into high molecular mass complexes derived from the matrix that also contained chondroitin sulfate, fibronectin, hyaluronan, and collagens I and IV. Enzymatic digestion with proteinases liberated sCD44 from the high molecular mass complex. Consistent with the homology of CD44 to proteoglycan core and link proteins, these data suggest that CD44 spontaneously released from normal bronchial epithelial cells can accumulate as an integral component of the matrix, where it may play a role in the organization of matrices and in anchoring growth factors and chemokines to the matrix. Increases in plasma CD44 during immune activation and tumor progression therefore may be a manifestation of the matrix remodeling that occurs in the face of the enhanced proteolytic activity associated with infection, inflammation, and tumor metastasis, leading to alterations in cell-matrix interactions.Cell-matrix interactions are critical for determination of cellular behavior. Some cells exhibit an extensive, highly organized pericellular matrix associated with the cell surface (1). On the other hand, the extracellular matrix (ECM) 1 contains secreted molecules that are immobilized in the extracellular spaces and regulates the function of almost all cells. The interaction of cells with the matrix is mainly mediated by adhesion molecules. CD44 is a widely expressed family of adhesion receptors that range in molecular mass from 80 to 250 kDa and that represent alternatively spliced and post-translationally modified products of a single gene (2). The most common form, referred to as hematopoietic CD44, has an apparent molecular mass of 80 -100 kDa and does not contain differentially spliced exons. CD44 isoforms expressing variant exons are mainly restricted to epithelia, activated lymphocytes, and tumor cells (3). CD44 is a major receptor for hyaluronan (HA), a glycosaminoglycan that is ubiquitously distributed in the ECM (4). In addition, proteoglycan forms of CD44 bind fibronectin (5), collagen (6), growth factors and cytokines (7), as well as matrix metalloproteinase-9 (8). In normal tissues, CD44 appears to play a role in regulating the metabolism of hyaluronan. However, data have accumulated that indicate a prominent role for CD44 in different pathologic states, including autoimmune and chronic inflammatory diseases (9 -13) as well as tumor grow...

Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

“…5D,5E). A major band at approximately 60 kDa was identified, which corresponds to the known size of soluble CD44 [24]. Soluble CD44 amounts were significantly decreased by HA and anti-MIF antibody treatment (p < 0.001, Fig.…”

“…Activation of cell surface CD74 requires interaction with CD44, a major adhesion molecule expressed in most cell types that has a strong affinity for hyaluronan (HA) [22,23]. CD44's extracellular domain is cleaved by membrane bound matrix metalloproteinases [24] and the resulting soluble CD44 reported as the most dominant form of CD44 expressed in tumors [25]. …”

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

“…MMP-14 can shed CD44, and the intracellular CD44 fragment subsequently generated by presenilin/␥-secretase action may function as a transcription factor (70,86). In turn, the soluble CD44/CSPG may modulate tumor growth and spreading (87,88) in an analogous fashion to other liberated tumor cell surface proteoglycans (89,90). Because MMP-14 is initially up-regulated by the ␣ 2 ␤ 1 integrin, this integrin may modulate CD44 shedding and subsequent signaling by liberated CD44 domains.…”

Soluble CD44 Interacts with Intermediate Filament Protein Vimentin on Endothelial Cell Surface

“…CD44 is involved in pathological angiogenesis, as its expression is elevated in tumor vasculature, and CD44 expression can be induced in cultured ECs by angiogenic growth factors [3] Furthermore, CD44 knockout mice show reduced vascularisation of tumor xenografts and Matrigel plugs [4]. In addition to cell surface expression, CD44 is present in soluble form in lymph and serum [5] or bound to extracellular matrix [6]. Soluble CD44 is generated either by alternative splicing [7] or, more importantly, by ectodomain shedding by matrix metalloproteases [8], [9].The size of shed CD44 is highly heterogeneous because of glycosylations and variant exons [5], [9]–[11].…”