title: Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.
abstract: In Caenorhabditis elegans, mutations in the lin-2 gene inactivate the LET-23 receptor tyrosine kinase/Ras/MAP kinase pathway required for vulval 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 have 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 lateral and/or basal plasma membrane domains in different epithelial cell types. We detect in a yeast two-hybrid screen that the PDZ domain of hCASK binds to the heparan sulfate proteoglycan syndecan-2. This interaction is confirmed using in vitro binding assays and immunofluorescent colocalization. Furthermore, we demonstrate that hCASK binds the actin-binding protein 4.1. Syndecans are known to bind extracellular matrix, 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 multidomain structure enables it to act as a scaffold at the membrane, potentially recruiting multiple proteins and coordinating signal transduction.
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Cohen
authors.forename: D F
authors.initials: DF
authors.lastname: Woods
authors.forename: S M
authors.initials: SM
authors.lastname: Marfatia
authors.forename: Z
authors.initials: Z
authors.lastname: Walther
authors.forename: A H
authors.initials: AH
authors.lastname: Chishti
authors.forename: J M
authors.initials: JM
authors.lastname: Anderson
authors.forename: D F
authors.initials: DF
authors.lastname: Wood
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins / Q000378:metabolism; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D004847:Epithelial Cells / Q000378:metabolism; D051528:Guanylate Kinases; D015801:Helminth Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009479:Neuropeptides; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism; D053669:Syndecan-2
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D015801:Helminth Proteins; C097978:Lin-2 protein, C elegans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009479:Neuropeptides; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; C508245:SDC2 protein, human; C508247:Sdc2 protein, rat; C028841:erythrocyte membrane band 4.1 protein; C120557:erythrocyte membrane protein band 4.1-like 1; C025957:spectrin-binding proteins; D013049:Spectrin; D053669:Syndecan-2; C106868:CASK kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases