Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lin-2 gene is required for the induction of the Caenorhabditis elegans vulva. Vulval development is initiated by a signal from the anchor cell that is transduced by a receptor tyrosine kinase/Ras pathway. We show that lin-2 acts in the vulval precursor cell P6.p, downstream of lin-3 EGF and upstream of let-60 ras, to allow expression of the 1 degrees cell fate. lin-2 encodes a protein of relative molecular mass 109,000 (LIN-2A) with regions of similarity to CaM kinase II and membrane-associated guanylate kinases. Mutant lin-2 transgenes designed to lack either protein kinase or guanylate kinase activity are functional, indicating that LIN-2A has a structural rather than an enzymatic role in vulval induction. Most or all identified membrane-associated guanylate kinases are components of cell junctions, including vertebrate tight junctions and arthropod septate junctions in epithelia. Thus, LIN-2A may be a component of the cell junctions of the epithelial vulval precursor cells that is required for signaling by the receptor tyrosine kinase LET-23. We propose that LIN-2A is required for the localization of one or more signal transduction proteins (such as LET-23) to either the basal membrane domain or the cell junctions, and that mislocalization of signal transduction proteins in lin-2 mutants interferes with vulval induction.
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PMID:The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins. 856 57

A transgenic mouse insertional mutant displayed the phenotype of altered cranial morphology with sex-linked cleft palate. We have cloned the disrupted genomic X-linked locus and report the identification of the mCASK gene. The gene is transcribed to produce two messages of 4.5 and 9.5 kb expressed during development and in adult tissues, particularly the brain. We describe the isolation of two differentially spliced mouse cDNAs from the locus (mCASK-A and mCASK-B). The mCASK-B cDNA probably represents the full-length product of the 4.5-kb transcript. The identical N-termini of the predicted encoded proteins (mCASK-A and -B) are highly homologous to Ca2+/calmodulin-dependent protein kinase II, while the deduced C-terminus of mCASK-B is highly homologous to a family of multidomain proteins containing a guanylate kinase motif, the MAGUK proteins. mCASK-B is a new member of an emerging family of genes in which the encoded proteins combine these domains, termed here, the CAMGUKs, including rat CASK, Caenorhabditis elegans lin-2, and Drosophila caki/camguk. The CAMGUKs are likely to be effectors in signal transduction as regulatory partners of transmembrane molecules, modulated by calcium and nucleotides. The transgene in this mutant mouse line integrated into an intron that bisects the encoded calmodulin-binding domain, a potentially important regulatory domain of the predicted protein, generating hybrid transcripts.
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PMID:Murine CASK is disrupted in a sex-linked cleft palate mouse mutant. 978 75

CASK, an adaptor protein of the plasma membrane, is composed of an N-terminal calcium/calmodulin-dependent protein (CaM) kinase domain, central PSD-95, Dlg, and ZO-1/2 domain (PDZ) and Src homology 3 (SH3) domains, and a C-terminal guanylate kinase sequence. The CaM kinase domain of CASK binds to Mint 1, and the region between the CaM kinase and PDZ domains interacts with Velis, resulting in a tight tripartite complex. CASK, Velis, and Mint 1 are evolutionarily conserved in Caenorhabditis elegans, in which homologous genes (called lin-2, lin-7, and lin-10) are required for vulva development. We now demonstrate that the N-terminal CaM kinase domain of CASK binds to a novel brain-specific adaptor protein called Caskin 1. Caskin 1 and a closely related isoform, Caskin 2, are multidomain proteins containing six N-terminal ankyrin repeats, a single SH3 domain, and two sterile alpha motif domains followed by a long proline-rich sequence and a short conserved C-terminal domain. Unlike CASK and Mint 1, no Caskin homolog was detected in C. elegans. Immunoprecipitations showed that Caskin 1, like Mint 1, is stably bound to CASK in the brain. Affinity chromatography experiments demonstrated that Caskin 1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin 1, suggesting that CASK and Caskin 1 coat the cytoplasmic tails of neurexins and other cell-surface proteins. Detailed mapping studies revealed that Caskin 1 and Mint 1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. Our data suggest that in the vertebrate brain, CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1 that may couple CASK to distinct downstream effectors.
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PMID:CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. 1204 31

Membrane-associated guanylate kinase (MAGUK) proteins are major determinants of the organization of ion channels in the plasma membrane in various cell types. Here, we investigated the interaction between the MAGUK protein SAP97 and cardiac Kv4.2/3 channels, which account for a large part of the outward potassium current, I(to), in heart. We found that the Kv4.2 and Kv4.3 channels C termini interacted with SAP97 via a SAL amino acid sequence. SAP97 and Kv4.3 channels were colocalized in the sarcolemma of cardiomyocytes. In CHO cells, SAP97 clustered Kv4.3 channels in the plasma membrane and increased the current independently of the presence of KChIP and dipeptidyl peptidase-like protein-6. Suppression of SAP97 by using short hairpin RNA inhibited I(to) in cardiac myocytes, whereas its overexpression by using an adenovirus increased I(to). Kv4.3 channels without the SAL sequence were no longer regulated by Ca2+/calmodulin kinase (CaMK)II inhibitors. In cardiac myocytes, pull-down and coimmunoprecipitation assays showed that the Kv4 channel C terminus, SAP97, and CaMKII interact together, an interaction suppressed by SAP97 silencing and enhanced by SAP97 overexpression. In HEK293 cells, SAP97 silencing reproduced the effects of CaMKII inhibition on current kinetics and suppressed Kv4/CaMKII interactions. In conclusion, SAP97 is a major partner for surface expression and CaMKII-dependent regulation of cardiac Kv4 channels.
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PMID:Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. 1932 57