CASK and Protein 4.1 Support F-actin Nucleation on Neurexins

Abstract

Rearrangements of the actin cytoskeleton are involved in a variety of cellular processes from locomotion of cells to morphological alterations of the cell surface. One important question is how local interactions of cells with the extracellular space are translated into alterations of their membrane organization. To address this problem, we studied CASK, a member of the membraneassociated guanylate kinase homologues family of adaptor proteins. CASK has been shown to bind the erythrocyte isoform of protein 4.1, a class of proteins that promote formation of actin/spectrin microfilaments. In neurons, CASK also interacts via its PDZ domain with the cytosolic C termini of neurexins, neuron-specific cell-surface proteins. We now show that CASK binds a brain-enriched isoform of protein 4.1, and nucleates local assembly of actin/spectrin filaments. These interactions can be reconstituted on the cytosolic tail of neurexins. Furthermore, CASK can be recovered with actin filaments prepared from rat brain extracts, and neurexins are recruited together with CASK and protein 4.1 into these actin filaments. Thus, analogous to the PDZdomain protein p55 and glycophorin C at the erythrocyte membrane, a similar complex comprising CASK and neurexins exists in neurons. Our data suggest that intercellular junctions formed by neurexins, such as junctions initiated by ␤-neurexins with neuroligins, are at least partially coupled to the actin cytoskeleton via an interaction with CASK and protein 4

Whirlin complexes with p55 at the stereocilia tip during hair cell development

“…Whirlin has been shown to interact with a related MAGUK protein, CASK, mediated by whirlin's PDZ3 domain and the guanylate kinase-like (GUK) domain of CASK (11). Moreover, CASK interacts with a brain-enriched isoform of protein 4.1, 4.1N, and the transmembrane protein neurexin to form a tripartite complex that links cell-surface proteins to the actin cytoskeleton and promotes local assembly of actin͞spectrin filaments in neurons (12). Both p55 and CASK carry HOOK domains that mediate interaction with protein 4.1 as well as a PDZ domain that interacts with the cytoplasmic domain of cell-surface molecules.…”

“…It appears that p55 plays a wider role in actin cytoskeletal assembly beyond its known erythrocyte function. In keeping with current models of MAGUK protein complexes that mediate actin cytoskeleton assembly (12,14), it will be important to determine any cell-surface proteins, analogous to glycophorin C, to which p55 binds in stereocilia and which may mediate extracellular signals controlling actin polymerization and stereocilia organization. p55 and 4.1R signal is detected in domains at the apical hair cell surface that do not express whirlin (8)(9)(10).…”

Nephrin Forms a Complex with Adherens Junction Proteins and CASK in Podocytes and in Madin-Darby Canine Kidney Cells Expressing Nephrin

“…46 CD2AP binds actin 47 and has been suggested to link nephrin to the actin cytoskeleton. 39 CASK may also participate in linking nephrin to actin, as CASK has previously been shown to connect other membrane proteins, eg, syndecan-2 44 and neurexins, 48 to the actin cytoskeleton.…”

Neurexin-1α Contributes to Insulin-containing Secretory Granule Docking

“…In neurons, NRXN seeds the assembly of the exocytotic machinery through interactions with Mint 1 (13), Velis (13,14), CASK (17,18,45), syntaxin 1 (15), and Munc18 (14). Consistent with NRXN being a constituent of the insulin granule submembrane secretory apparatus in ␤ cells, we found coprecipitation of NRXN1␣ with the submembrane exocytotic proteins syntaxin 1, CASK, and Munc18 (Fig.…”