Abstract
Laminin-2, a heterotrimer composed of alpha2, beta1, and gamma1 subunits, is the primary laminin isoform found in muscle and peripheral nerve and is essential for the development and stability of basement membranes in these tissues. Expression of a domain VI-truncated laminin alpha2-chain results in muscle degeneration and peripheral nerve dysmyelination in the dy2J dystrophic mouse. We have expressed amino-terminal domains VI through IVb of the laminin alpha2-chain, as well as its laminin-1 alpha1-chain counterpart, to identify candidate cell-interactive functions of this critical region. Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. In addition, we found that the laminin alpha2-chain short arm supported neurite outgrowth independent of other laminin-2 subunits. A heparin/heparan sulfate binding activity was also localized to this region of the laminin alpha2 subunit. These data provide the first evidence that domain VI of the laminin alpha2-chain mediates interactions with cell surface receptors and suggest that these integrin and heparin binding sites, alone or in concert, may play an important role in muscle and peripheral nerve function.
Highlights
Members of the laminin family of glycoproteins are thought to be important for the development and stability of basement membranes, both through architecture-forming interactions with other laminins and matrix components and through recognition of cell signaling molecules such as integrins
The repertoire of known laminin ␣2-chain functions have far all been associated with its long arm; attention has recently focused on possible function(s) of the short arm following the identification of muscular dystrophies in which the amino-terminal short arm of the ␣2-chain is truncated or otherwise mutated (18 –21)
Expression and Characterization of Laminin ␣-Chain Short Arm Proteins—Previous studies investigating the role of laminin-2 in cell adhesion and signaling have used the entire threechain ϳ800-kDa molecule [11,12,13,14, 31,32,33,34]
Summary
Members of the laminin family of glycoproteins are thought to be important for the development and stability of basement membranes, both through architecture-forming interactions with other laminins and matrix components and through recognition of cell signaling molecules such as integrins. In the dy2J mouse, muscular dystrophy develops as the result of a truncation in ␣2-chain domain VI within the context of an otherwise functional heterotrimeric laminin molecule2 [18, 19] This mutation leads to peripheral nerve defects, seen in the allelic dy mouse where the laminin ␣2 subunit is completely absent [7, 8]. We show that the ␣2-chain short arm contains heparin binding sites that may mediate interactions with cell surface proteoglycans or other charged glycosaminoglycans These shared integrin recognition sites and heparin-binding activities may act alone or in concert with ␣-chain domain VI polymer-forming sites3 [25, 26], modulating cell activity and matrix architecture
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