HUMAN CASK LIN-2 BINDS SYNDECAN-2 AND PROTEIN-4.1 AND LOCALIZES TO THE BASOLATERAL MEMBRANE OF EPITHELIAL-CELLS/

In Caenorhabditis elegans, mutations in the lin-2 gene inactivate the LET-23 receptor tyrosine kinase/Ras/MAP kinase pathway required for vu lval cell differentiation. One function of LIN-2 is to localize LET-23 to the basal membrane domain of vulval precursor cells. LIN-2 belongs to the membrane-associated guanylate kinase family of proteins. We ha ve cloned and characterized the human homolog of LIN-2, termed hCASK, and Northern and Western blot analyses reveal that it is ubiquitously expressed. Indirect immunofluorescence localizes CASK to distinct late ral and/or basal plasma membrane domains in different epithelial cell types. We detect in a yeast two-hybrid screen that the PDZ domain of h CASK binds to the heparan sulfate proteoglycan syndecan-2. This intera ction is confirmed using in vitro binding assays and immunofluorescent colocalization. Furthermore, we demonstrate that hCASK binds the acti n-binding protein 4.1. Syndecans are known to bind extracellular matri x, and to form coreceptor complexes with receptor tyrosine kinases. We speculate that CASK mediates a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with protein 4.1. Like other membrane-associated guanylate kinases, its mul tidomain structure enables it to act as a scaffold at the membrane, po tentially recruiting multiple proteins and coordinating signal transdu ction.