The Laminins and their Receptors

Sammanfattning: Basement membranes are thin extracellular sheets that surround muscle, fat and peripheral nerve cells and underlay epithelial and endothelial cells. Laminins are one of the main protein families of these matrices. Integrins and dystroglycan are receptors for laminins, connecting cells to basement membranes. Each laminin consists of three different chains, (?, ?, ?). Laminin-1 (?1?1?1) was the first laminin to be found and is the most frequently studied. Despite this, it was unclear where its ?1 chain was expressed. A restricted distribution of the ?1 chain in the adult epithelial basement membranes was demonstrated in the present study. In contrast, dystroglycan was found to have a much broader distribution. Dystroglycan is an important receptor for ?2-laminins in muscle, but binds also ?1-laminins. The more ubiquitous ?5-laminins were also shown to bind dystroglycan, but with distinctly lower affinity than ?1- and ?2- laminins. The biological roles of different laminin isoforms have been investigated. Differences were found in the capacity of various tested laminins to promote epithelial cell adhesion. The ?5-laminins were potent adhesive substrates, a property shown to be dependent on ?3 and ?6 integrins. Each receptor alone could promote efficient epithelial cell adhesion to ?5-laminins. Yet, only ?6 integrin and in particular the ?6A cytoplasmic splice variant could be linked to laminin-mediated activation of a mitogen-activated protein kinase (MAP kinase) pathway. Attachment to either ?1- or ?5-laminins activated extracellular-signal regulated kinase (ERK) in cells expressing the integrin ?6A variant, but not in cells expressing ?6B. A new role for dystroglycan as a suppressor of this activation was demonstrated. Dystroglycan antibodies, or recombinant fragments with high affinity for dystroglycan, decreased ERK activation induced by integrin ?6 antibodies. Integrin ?v?3 was identified as a novel co-receptor for ?5-laminin trimers. Cell attachment to ?5-laminins was found to facilitate growth factor induced cell proliferation. This proliferation could be blocked by antibodies against integrin ?v?3 or by an inhibitor of the MEK/ERK pathway. Therefore, integrin ?v?3 binding to ?5-laminins could be of biological significance.