Collagen XXIII, Novel Ligand for Integrin α2β1 in the Epidermis

Abstract

Cellular receptors for collagens belong to the family of ␤ 1 integrins. In the epidermis, integrin ␣ 2 ␤ 1 is the only collagenbinding integrin present. Its expression is restricted to basal keratinocytes with uniform distribution on the cell surface of those cells. Although ␣ 2 ␤ 1 receptors localized at the basal surface interact with basement membrane proteins collagen IV and laminin 111 and 332, no interaction partners have been reported for these integrin molecules at the lateral and apical membranes of basal keratinocytes. Solid phase binding and surface plasmon resonance spectroscopy demonstrate that collagen XXIII, a member of the transmembrane collagens, directly interacts with integrin ␣ 2 ␤ 1 in an ion-and conformation-dependent manner. The two proteins co-localize on the surface of basal keratinocytes. Furthermore, collagen XXIII is sufficient to induce adhesion and spreading of keratinocytes, a process that is significantly reduced in the absence of functional integrin ␣ 2 ␤ 1 .Collagen XXIII belongs to the class of transmembrane collagens in type II orientation, which comprises the collagens XIII, XVII, XXIII, and XXV and other related proteins such as ectodysplasin A, class A macrophage scavenger receptors, and the colmedins (1, 2). Collagen XXIII forms homotrimers consisting of a short intracellular domain, a single-pass transmembrane domain and three extracellular collagen domains interrupted by short noncollagenous sequences (3, 4). It exists either as a full-length, membrane-anchored protein or as a soluble ectodomain. The proteolytic processing releasing the ectodomain is mediated by furin and is regulated by the plasma membrane microenvironment (5). Collagen XXIII is expressed in the epidermis and other epithelia such as those in the tongue, gut, and lung but also in the brain and kidney (4). In prostate, collagen XXIII expression was shown to correlate with tumor progression (6).Four integrins, ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , ␣ 10 ␤ 1 , and ␣ 11 ␤ 1 bind native collagens (7). This ␤ 1 subunit-containing subclass of integrins is characterized by the presence of an inserted domain (I domain) with homology to von Willebrand factor A domains in their ␣-subunit, which harbors the ligand-binding site (8, 9). The integrins ␣ 10 ␤ 1 and ␣ 11 ␤ 1 have a restricted expression pattern on differentiated chondrocytes and developing muscle cells (10, 11), whereas ␣ 1 ␤ 1 and ␣ 2 ␤ 1 show a broader distribution, with integrin ␣ 1 ␤ 1 being predominantly expressed by cells of mesenchymal origin and integrin ␣ 2 ␤ 1 by epithelial cells and platelets. In vitro studies suggested an implication of integrin ␣ 2 ␤ 1 in cell attachment and migration (12, 13), generation of mechanical forces and contraction of collagen matrices (14), induction of collagenase activity and matrix remodeling (15, 16), as well as angiogenesis (17) and epithelial branching morphogenesis (18). Mice lacking the integrin ␣ 2 subunit exhibit defects in mammary gland branching morphogenesis (19), delayed platelet aggregation and formation of unstable t...

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A role for collagen XXIII in cancer cell adhesion, anchorage-independence and metastasis

“…Relatedly, transmembrane collagens are known cell adhesion molecules, present in hemidesmosomes (collagen XVII) or focal adhesions (collagen XIII), and have diverse binding partners (Diaz et al 1990, Franzke et al 2003, Franzke et al 2005, Hagg et al 2001, Tu et al 2002, Veit et al 2007). Collagen XXIII has recently been shown to bind α2β1 integrin in keratinocytes (Veit et al 2011) and aids corneal epithelial cell binding to collagen IV and Matrigel (Gordon 2005). …”