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J. Cell Biol.,
Volume 142, Number 1, July 13, 1998 129-138
* Department of Cell Biology, 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.
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
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