The liberation of CD44

Abstract

CD44 was once thought to simply be a transmembrane adhesion molecule that also played a role in the metabolism of its principal ligand hyaluronan. Investigations of CD44 over the past ∼20 yr have established additional functions for CD44, including its capacity to mediate inflammatory cell function and tumor growth and metastasis. It has also become evident that intricate posttranslational modifications of CD44 regulate the affinity of the receptor for its ligands. In this review, we focus on emerging evidence that functional fragments of the cytoplasmic and ectodomain of CD44 can be liberated by enzymatic modification of cell surfaces as well as of cell-associated matrix. Based on the evidence discussed, we propose that CD44 exists in three phases, as a transmembrane receptor, as an integral component of the matrix, and as a soluble protein found in body fluids, each with biologically significant functions of which some are shared and some distinct. Thus, CD44 represents a model for understanding posttranslational processing and its emerging role as a general mechanism for regulating cell behavior.

The immune system and cardiac repair

“…Increased turnover of extracellular matrix is a hallmark of tissue injury and results in generation of degradation products. Hyaluronan, a ubiquitously present constituent of the extracellular matrix [281], exists as a high molecular weight polymer under physiologic conditions, but undergoes degradation resulting in accumulation of lower molecular weight species after tissue injury. Hyaluronan fragments induce the expression of a variety of inflammatory genes by endothelial cells and macrophages [282], including chemokines and cytokines, and may play an important role in regulating inflammatory processes.…”

Podosome-type adhesions and focal adhesions, so alike yet so different

“…substrate through its affinity for hyaluronan, a glycosaminoglycan constituent of extracellular matrix, but also potentially through its affinity for other ligands such as osteopontin, collagens and matrix metalloproteases ( ). Since the actin core seems to Cichy and Pure, 2003 appear before formation of the integrin rich surrounding ring in Src-transformed BHK cells, CD44 could play the role of an initial adhesion. Similarly, in addition to integrins, proteoglycan, glycosaminoglycan receptors were recently reported to localize at focal adhesions and induce an initial adhesion mediated by hyaluronate before the formation of adhesion structures driven by integrins (Cohen et recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration.…”

Mechanoregulation of gene expression in fibroblasts

“…For example, collagen I mRNA synthesis was greater in human lung fibroblasts stretched on laminin and elastin than in fibroblasts stretched on fibronectin (Breen, 2000). Cell-ECM interaction may directly regulate cell functions through cell surface receptor-mediated signaling mainly via integrins and non-integrin receptors, syndecan, and CD44 (Hynes, 1992;Couchman et al, 2001;Cichy and Pure, 2003). Through αβ pairing, specific integrin ligands can interact with ECM proteins and different ECM macromolecules may selectively stimulate specific types of signal transduction pathways for the modulation of gene expression (Jalali et al, 2001;Rosso et al, 2004).…”

“…CD44 is transmembrane protein that serves as an adhesion molecule for hyaluronan (HA), an ECM component (Aruffo et al, 1990;Nagano and Saya, 2004). CD44-dependent cell-matrix interaction and signaling pathway are regulated by its proteolytic cleavage (Lesley and Hyman, 1998;Cichy and Pure, 2003). The cleavage generates CD44ICD (CD44 intracellular domain), which acts as a signal transduction molecule (Fig.…”