The Laminin–Nidogen Complex is a Ligand for a Specific Splice Isoform of the Transmembrane Protein Tyrosine Phosphatase LAR

Leukocyte antigen–related protein (LAR) is a prototype for a family of transmembrane protein tyrosine phosphatases whose extracellular domain is composed of three Ig and several fibronectin type III (FnIII) domains. Complex alternative splicing of the LAR-FnIII domains 4–8 has been observed. The extracellular matrix laminin–nidogen complex was identified as a ligand for the LAR-FnIII domain 5 (Fn5) using a series of GST-LAR-FnIII domain fusion proteins and testing them in in vitro ligand-binding assays. LAR– laminin–nidogen binding was regulated by alternative splicing of a small exon within the LAR-Fn5 so that inclusion of this exon sequence resulted in disruption of the laminin–nidogen-binding activity. Long cellular processes were observed when HeLa cells were plated on laminin–nidogen, but not when plated on a fibronectin surface. Indirect immunofluorescent antibody staining revealed high expression of LAR in a punctate pattern, throughout the length of these cellular processes observed on laminin–nidogen. Antibody-induced cross-linking of LAR inhibited formation of these cellular processes, and inhibition was correlated with changes in cellular actin cytoskeletal structure. Thus, LAR–laminin–nidogen binding may play a role in regulating cell signaling induced by laminin–nidogen, resulting in cell morphological changes.