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© The Rockefeller University Press, 0021-9525/1998//129 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 129-138

Articles

Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells



Alexandra R. Cohen*, Daniel F. Wood{ddagger}, Shirin M. Marfatia§, Zenta Walther, Athar H. Chishti§, and James Melvin Anderson*,||

* Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520; {ddagger} Developmental Biology Center, University of California, Irvine, California 92717; § Department of Biomedical Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135; and || Department of Internal Medicine and Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520

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.

Key Words: CASK • LIN-2 • syndecan • protein 4.1 • MAGUK

Abbreviations used in this paper: CAMK, calcium/calmodulin-dependent protein kinase; GST, glutathione-S-transferase; GUK, guanylate kinase; MAGUK, membrane-associated guanylate kinase; RTK, receptor tyrosine kinase; SH3, Src homology 3.

Address all correspondence to James M. Anderson, 1080 LMP, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, 1080 LMP, P.O. Box 208019, New Haven, CT 06520-8019. Tel: 203-785-7312. Fax: 203-785-7273; E-mail: james.anderson{at}yale.edu


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