Fumiharu Yokoyama

Functional sites in the laminin alpha chains.

Laminins, heterotrimers composed of α, β, and γ chains, are multifunctional glycoproteins present in basement membranes. Laminins, the most important component of basement membranes during basement membrane assembly in early development, are involved in various biological activities such as cell adhesion, migration, growth, differentiation, tumor metastasis, and angiogenesis. Fully 15 laminin isoforms have been identified and are tissue- and/or developmental stage-specifically expressed. Integrins, dystroglycan, syndecans, and the other several cell surface molecules are cellular receptors for laminins. The globular domains located in the N- and C-terminus of the laminin alpha chains are critical for interactions with the cellular receptors. There are highly conserved functional sites and chain-specific functional sites among the laminin α chains. Additionally, laminins are processed by specific endogenous proteases and the processing regulates laminin functions. Binding of the functional sequences in laminins to the cellular receptors triggers intracellular signaling, followed by inducing various cell activities including cell spreading and migration. Laminins possess multifunctional sequences and are key molecules that determine cell fate.

Lamininα3 LG4 Module Induces Keratinocyte Migration: Involvement of Matrix Metalloproteinase-9

Abstract Laminin α 3 chain, a functionally key subunit of laminin-5, contains a large globular module (G module) which consists of a tandem repeat of five homologous LG modules (LG1∼ 5). We previously demonstrated that the LG4 module of laminin α 3 chain (α 3 LG4) induces a matrix metalloproteinase-1 (MMP-1) expression through the interaction with syndecans leading to MAPK activation/IL-1β expression signaling loop (Utani et al., J. Biol. Chem. 278, 34483–34490, 2003). Here, we show that a recombinant α 3 LG4 and synthetic peptides containing syndecan binding motif induced a cell motility and a MMP-9 expression in ketarinocytes. The synthetic peptide (A3G756)-induced cell migration and MMP-9 upregulation were inhibited by each application of a heparin and an IL-1 receptor antagonist (IL-1RA), suggesting the involvement of syndecans and IL-1β autocrine. Furthermore, the A3G756-induced cell motility was inhibited by an MMP-9 inhibitor and a neutralizing antibody of MMP-9, indicating induced cell motility was dependent on an MMP-9 activity. Taken these together, laminin-5 α 3 LG4 module may play an important role in re-epithelialization at tissue remodeling.