UNIPROT:P43146 - FACTA Search

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Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor gene PTEN is mutated in a wide range of human cancers at a frequency roughly comparable with p53. In addition, germline PTEN mutations are associated with several dominant growth disorders. The molecular and cellular basis of these disorders has been elucidated by detailed in vivo genetic analysis in model organisms, in particular the fruit fly and mouse. Studies in the fly have shown that PTEN's growth regulatory functions are primarily mediated via its lipid phosphatase activity, which specifically reduces the cellular levels of phosphatidylinositol 3,4,5-trisphosphate. This activity antagonizes the effects of activated PI3-kinase in the nutritionally controlled insulin receptor pathway, thereby reducing protein synthesis and restraining cell and organismal growth, while also regulating other biological processes, such as fertility and ageing. Remarkably, this range of functions appears to be conserved in all higher organisms. PTEN also plays a role as a specialized cytoskeletal regulator, which, for example, is involved in directional movement of some migratory cells and may be important in metastasis. Furthermore, conditional knockouts in the mouse have recently revealed functions for PTEN in other processes, such as cell type specification and cardiac muscle contractility. Genetic approaches have therefore revealed a surprising diversity of global and cell type-specific PTEN-regulated functions that appear to be primarily controlled by modulation of a single phosphoinositide. Together with evidence from studies in cell culture that suggests links between PTEN and other growth regulatory genes such as p53, these studies provide new insights into PTEN-linked disorders and are beginning to suggest potential clinical strategies to combat these and other diseases.
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PMID:PTEN: tumour suppressor, multifunctional growth regulator and more. 1292 88

Unopposed PI3-kinase activity and 3'-phosphoinositide production in Jurkat T cells, due to a mutation in the PTEN tumour suppressor protein, results in deregulation of PH domain-containing proteins including the serine/threonine kinase PKB/Akt. In Jurkat cells, PKB/Akt is constitutively active and phosphorylated at the activation-loop residue (Thr308). 3'-phosphoinositide-dependent protein kinase-1 (PDK-1), an enzyme that also contains a PH domain, is thought to catalyse Thr308 phosphorylation of PKB/Akt in addition to other kinase families such as PKC isoforms. It is unknown however if the loss of PTEN in Jurkat cells also results in unregulated PDK-1 activity and whether such loss impacts on activation-loop phosphorylation of other putative PDK-1 substrates such as PKC. In this study we have addressed if loss of PTEN in Jurkat T cells affects PDK-1 catalytic activity and intracellular localisation. We demonstrate that reducing the level of 3'-phosphoinositides in Jurkat cells with pharmacological inhibitors of PI3-kinase or expression of PTEN does not affect PDK-1 activity, Ser241 phosphorylation or intracellular localisation. In support of this finding, we show that the levels of PKC activation-loop phosphorylation are unaffected by reductions in the levels of 3'-phosphoinositides. Instead, the dephosphorylation that occurs on PKB/Akt at Thr308 following reductions in 3'-phosphoinositides is dependent on PP2A-like phosphatase activity. Our finding that PDK-1 functions independently of 3'-phosphoinositides in T cells is also confirmed by studies in HuT-78 T cells, a PTEN-expressing cell line with undetectable levels of 3'-phosphoinositides. We conclude therefore that loss of PTEN expression in Jurkat T cells does not impact on the PDK-1/PKC pathway and that only a subset of kinases, such as PKB/Akt, are perturbed as a consequence PTEN loss.
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PMID:Loss of PTEN expression does not contribute to PDK-1 activity and PKC activation-loop phosphorylation in Jurkat leukaemic T cells. 1782 53

The Discs Large (Dlg) protein is known to be involved in the regulation of cellular proliferation and polarity in a variety of tissues. The human homologue DLG1 is thought to be a tumour suppressor, through formation of a complex with the APC (adenomatous polyposis coli) protein, causing negative regulation of the cell cycle. An alternative oncogenic role has also been proposed, in which the PI3-kinase pathway is activated under the influence of the adenovirus E4 ORF1 protein. The differing roles seem to be related to differences in the precise pattern of expression. However, the biochemical pathways involved in regulating DLG1 function during different phases of the cell cycle remain unclear. In this study we show that phosphorylation is a major post-translational modification of the protein and it affects both location and function. DLG1 lies at the cellular junctions in G1, is enriched in the cytoplasm in S phase and locates to the mitotic spindle in M phase. We also show that DLG1 is phosphorylated by both CDK1 and CDK2 on Ser158 and Ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on Ser158 and Ser442 in its putative nuclear functions as a tumour suppressor. In addition, the mutants at these sites demonstrate different half-lives as well as different susceptibilities to ubiquitylation, suggesting a role for these phosphorylation events in controlling DLG1 protein stability. These findings establish phosphorylation events as key regulators of DLG1 localisation and function.
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PMID:CDK phosphorylation of the discs large tumour suppressor controls its localisation and stability. 1906 88

Cilia are hair-like cellular protrusions important in many aspects of eukaryotic biology. For instance, motile cilia enable fluid movement over epithelial surfaces, while primary (sensory) cilia play roles in cellular signalling. The molecular events underlying cilia dynamics, and particularly their disassembly, are not well understood. Phosphatase and tensin homologue (PTEN) is an extensively studied tumour suppressor, thought to primarily act by antagonizing PI3-kinase signalling. Here we demonstrate that PTEN plays an important role in multicilia formation and cilia disassembly by controlling the phosphorylation of Dishevelled (DVL), another ciliogenesis regulator. DVL is a central component of WNT signalling that plays a role during convergent extension movements, which we show here are also regulated by PTEN. Our studies identify a novel protein substrate for PTEN that couples PTEN to regulation of cilia dynamics and WNT signalling, thus advancing our understanding of potential underlying molecular etiologies of PTEN-related pathologies.
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PMID:PTEN regulates cilia through Dishevelled. 2639 23

Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3-kinase like-kinase (PIKK) family of proteins. ATM is a well-established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm^-/- Smg1^gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm^-/- Smg1^gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.
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PMID:SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress. 3156 65