Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C-CAMs are epithelial cell-adhesion molecules of the immunoglobulin supergene family with sequences highly homologous to carcinoembryonic antigen (CEA). C-CAMs and their human homologues, biliary glycoproteins, are unique among the CEA-family proteins in that they have cytoplasmic domains. Furthermore, alternative splicing generates C-CAM isoforms with different cytoplasmic domains, suggesting that the cytoplasmic domains of C-CAM may play important roles in regulating the function or functions of C-CAM. By using both sense and antisense approaches, we have shown that C-CAM1 is a tumour suppressor in prostate carcinogenesis. This observation raises the possibility that the cytoplasmic domain of C-CAM1 may be involved in signal transduction or interaction with cytoskeletal elements to elicit the tumour suppressor function. The cytoplasmic domain of C-CAM1 contains several potential phosphorylation sites, including putative consensus sequences for cyclic AMP-dependent kinase and tyrosine kinase. One of the potential tyrosine phosphorylation sites is located within the antigen-receptor homology (ARH) domain. The ARH domain of the membrane-bound IgM molecule is necessary for signal transduction in B-cells. These structural features suggest that the cytoplasmic domain of C-CAM1 may be important for signal transduction. To test this possibility, we generated several site-directed C-CAM1 mutants and tested their ability to support adhesion and their abilities to be phosphorylated in vivo. Results from these studies revealed that Tyr-488 is phosphorylated in vivo. However, replacing this tyrosine with phenylalanine did not significantly compromise its adhesion function. Similarly, Ser and Thr residues are phosphorylated in vivo, but deletion of the potential cyclic AMP-dependent kinase site did not significantly reduce the adhesion function. These results suggest that the kinase phosphorylation sites in the cytoplasmic domain of C-CAM1 are not required for the adhesion function. However, these phosphorylation sites are probably involved in the regulation of C-CAM-mediated signal transduction. Thus, there are probably distinct structural requirements for the adhesion and the signal transduction functions of C-CAM. Incidentally, a C-CAM1 deletion mutant containing a 10-amino-acid cytoplasmic domain was able to support adhesion activity. This is in contrast to our previous finding that a C-CAM isoform, C-CAM3, with a 6-amino-acid cytoplasmic domain could not support cell adhesion. This result indicates that the extra four amino acids, which are absent in C-CAM3 and contain a potential Ser/Thr phosphorylation site, are important for the adhesion function.
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PMID:Structure and function of C-CAM1: effects of the cytoplasmic domain on cell aggregation. 757 60

SSeCKS is a major protein kinase C substrate which has tumour suppressor activity in models of src- and ras-induced oncogenic transformation. The mitogenic regulatory activity of SSeCKS is likely manifested by its ability to bind key signalling proteins such as protein kinases C and A and calmodulin, and to control actin-based cytoskeletal architecture. Rat SSeCKS shares extensive homology with human Gravin, an autoantigen in myasthenia gravis that encodes kinase scaffolding functions and whose expression pattern in fibroblasts and nerves suggests a role in cell motility. Here, we analyse the expression of SSeCKS and Gravin in rodent and human fibroblast and epithelial cell lines using antibodies specific or crossreactive for SSeCKS or Gravin. SSeCKS expression was then analysed in developing mouse embryos and in adult tissues. In the foetal mouse, early SSeCKS protein expression (E10-11) is focused in the loose mesenchyme, luminal surface of the neural tube, notochord, early heart and pericardium, urogenital ridge, and dorsal and ventral sections of limb buds. In later stages (E12-14), SSeCKS is widely expressed in mesenchymal cells but is absent in the spinal ganglia. By E15, SSeCKS expression is ubiquitous, although the staining pattern varies from being striated within smooth muscle sarcomeres to filamentous in mesenchymal and select epithelial cells. In the adult mouse, SSeCKS staining is relatively ubiquitous, with highest expression in the gonads, smooth and cardiac muscle, lung, brain and heart. High expression is also detected in fibroblasts and nerve fibres as well as in more specialized cells such as glomerular mesangial cells and testicular Sertoli cells. SSeCKS expression in the rat testes correlates with the induction of puberty, and in mature mouse spermatozoa, SSeCKS is found in peripheral acrosome membranes and in a helix-like winding pattern within the midsection. Periodic enrichments of SSeCKS are found in sperm midsections and in developing axons, suggesting a role in architectural infrastructure. As with Gravin, high SSeCKS expression is absent in most epithelial cells; however, in contrast to Gravin, SSeCKS is expressed in Purkinje cells, cardiac muscle, macrophages and hepatic stellate cells, indicating overlapping yet distinct patterns of tissue expression in the SSeCKS/Gravin family. The data suggest roles for SSeCKS in the control of cytoskeletal and tissue architecture, formation of migratory processes and cell migration during embryogenesis.
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PMID:A role for SSeCKS, a major protein kinase C substrate with tumour suppressor activity, in cytoskeletal architecture, formation of migratory processes, and cell migration during embryogenesis. 1080 81

The spectrin-based membrane skeleton, a multi-protein scaffold attached to diverse cellular membranes, is presumed to be involved in the stabilization of membranes, the establishment of membrane domains as well as in vesicle trafficking and nuclear functions. Spectrin tetramers made of alpha- and beta-subunits are linked to actin microfilaments, forming a network that binds a multitude of proteins. The most prevalent alpha-spectrin subunit in non-erythroid cells, alphaII-spectrin, contains two particular spectrin repeats in its central region, alpha9 and alpha10, which host an Src homology 3 domain, a tissue-specific spliced sequence of 20 residues, a calmodulin-binding site and major cleavage sites for caspases and calpains. Using yeast two-hybrid screening of kidney libraries, we identified two partners of the alpha9-alpha10 repeats: the potential tumour suppressor Tes, an actin-binding protein mainly located at focal adhesions; and EVL (Ena/vasodilator-stimulated phosphoprotein-like protein), another actin-binding protein, equally recruited at focal adhesions. Interactions between spectrin and overexpressed Tes and EVL were confirmed by co-immunoprecipitation. In vitro studies showed that the interaction between Tes and spectrin is mediated by a LIM (Lin-11, Isl-1 and Mec3) domain of Tes and by the alpha10 repeat of alphaII-spectrin whereas EVL interacts with the Src homology 3 domain located within the alpha9 repeat. Moreover, we describe an in vitro interaction between Tes and EVL, and a co-localization of these two proteins at focal adhesions. These interactions between alphaII-spectrin, Tes and EVL indicate new functions for spectrin in actin dynamics and focal adhesions.
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PMID:AlphaII-spectrin interacts with Tes and EVL, two actin-binding proteins located at cell contacts. 1565 90