title: Matrix hyaluronan-activated CD44 signaling promotes keratinocyte activities and improves abnormal epidermal functions.
abstract: Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-Nγ, and phosphoinositide-specific phospholipases (phospholipases Cε and Cγ1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinase-AKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)-mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds.
authors.affiliation: Department of Medicine, University of California at San Francisco, and the Endocrine Unit, VA Medical Center, San Francisco, California. Electronic address: lilly.bourguignon@ucsf.edu.
authors.forename: Lilly Y W
authors.initials: LY
authors.lastname: Bourguignon
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D003599:Cytoskeleton / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000503:physiopathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology*; D018345:Mice, Knockout; D015398:Signal Transduction; D015595:Skin Aging; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein