Laminin‐332 and ‐511 in skin

Abstract

The extracellular matrix (ECM) was long thought to be merely a structural tissue support and ⁄ or a filter. However, recent studies have suggested that ECM proteins regulate many intracellular and extracellular events, including cell growth, cell adhesion, cell division, cell movement, and apoptosis. They do so through activation of several families of cell surface receptor, including the integrins and syndecans. The focus of this review is on two laminin isoforms expressed in the skin. Laminins are an important molecular component of the basement membranes in a variety of tissue types. They have a cruciform shape, and are composed of three chains-a, b, and c. Keratinocytes of the skin secrete numerous laminin isoforms, including laminin-511 and laminin-332. The latter are known to affect the behaviour of keratinocytes through binding to membrane-penetrating receptors (outside-in signal transduction). Conversely, the expression, secretion and assembly of lamininrich matrices is regulated by cell surface receptors through inside-out signal transduction. We will review how integrins regulate laminin matrix assembly and the signals elicited by laminins that support either migration or stable adhesion of keratinocytes. We will also discuss recent data indicating that laminins plays key regulatory roles in the development of skin appendages and contribute to the pathogenesis of skin cancer.

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…All of the laminins, with the exception of a1-laminins, undergo proteolytic cleavage of the LG domains and/or short arm. Laminin-3A32, the most heavily processed of all of the known laminins, can be cleaved by MT1-MMP and MMP-2 in the g2LEb domain, by plasmin, BMP-1, MT1-MMP and other enzymes in the g2LEa domain, by plasmin, MT1-MMP and other enzymes among a3LG3 and 4, and by MT1-MMP in the b3LE domain (reviewed in Sugawara et al 2008). Cleavage of the g2 short arm by MT1-MMP or MMP-2 appears to expose a cryptic site that promotes migration, possibly by releasing an EGF-containing fragment that binds to the EGF receptor (Giannelli et al 1997;Schenk et al 2003).…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…Over the past 20 years, the expression of integrins and extracellular matrix proteins in the skin has been characterized extensively (Watt 2002;Wilhelmsen et al 2006;Sugawara et al 2008;Breitkreutz et al 2009;Ko and Marinkovich 2010). In addition to the differences in ECM composition of upper and deep dermis ( Fig.…”

“…Laminin-511 (laminin-10; a5b1g1) is up-regulated in growing hair follicles and Lama5 -/ -skin shows a failure of hair germ elongation followed by complete hair follicle regression, defects that are not caused by cell detachment from the basement membrane (Li et al 2003). Whereas laminin-511 is primarily of importance in the hair follicle, knockout of laminin-a3, b3, and g2 chains of laminin-332 results in severe skin-blistering (Sugawara et al 2008). Laminin-332 is thus essential for adhesion of the epidermis to the basement membrane, consistent with human patients with laminin-332 mutations having junctional Epidermolysis bullosa.…”

“…Given the non-cell-autonomous roles of integrins, one can speculate that reduced epidermal integrin levels may affect other cell compartments, such as skin vasculature and pigmentation. Laminin-511 levels decline during aging and it has been suggested that this may contribute to age-related hair loss (Sugawara et al 2008).…”

Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

“…1A). For example, the globular (G) domain at the carboxy-terminal of the laminin α chain interacts with cell-surface receptors such as integrin, syndecan, and α-dystroglycan [13,[22][23][24]. In regard to the α3 laminin subunit, its G domain interacts with two integrins (α3β1 and α6 4 integrin) and syndecan [25,26].…”