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)

Netrin-1 attracts or repels growing axons during development. The UNC5 receptors mediate the repulsive response, either alone or in complex with DCC receptors. The signaling mechanisms activated by UNC5 are poorly understood. Here, we examined the role of Rho GTPases in UNC5a signaling. We found that UNC5a induced neurite outgrowth in N1E-115 neuroblastoma cells in a netrin-1- and Rac1-dependent manner. UNC5a lacking its cytoplasmic tail also mediated this effect. In fibroblasts, UNC5a was able to activate RhoA and to a lower extent Rac1 and Cdc42 in response to netrin-1. Using Fluorescence Resonance Energy Transfer (FRET) intermolecular probes, we visualized the spatial and temporal activation of Rac1, Cdc42 and RhoA in live N1E-115 cells expressing UNC5a during neurite outgrowth. We found that Rac1 but not Cdc42 was transiently activated at the leading edge of the cell during neurite initiation. However, at later times when well-developed neurites were formed, active RhoA was found in the cell body and at the base of the neuronal leading process in UNC5a-expressing cells. Together, these findings demonstrate that the netrin-1 receptor UNC5a is able to induce neurite outgrowth and to differentially activate RhoA and Rac1 during neurite extension in a spatial and temporal manner.
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PMID:Spatial and temporal activation of the small GTPases RhoA and Rac1 by the netrin-1 receptor UNC5a during neurite outgrowth. 1975 50

Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK-mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton.
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PMID:Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression. 2083 90

IgLONs are a family of four GPI-anchored cell adhesion molecules that regulate neurite outgrowth, synaptogenesis and may act as tumour suppressor genes. IgLONs are thought to function as monomers or homodimers and we have proposed that IgLONs also act as heterodimeric complexes termed Dimeric IgLONs or DIgLONs. Here we show that the initiation of neurite outgrowth is inhibited from a subset of chick embryonic day (E) 7 or 8 forebrain neurons when they are cultured on CHO cell lines expressing DIgLON:CEPU-1-OBCAM and DIgLON:CEPU-1-LAMP but not on CHO cells that express single IgLONs CEPU-1 or OBCAM. Surprisingly at the younger age of E6 forebrain neurons do not respond to DIgLONs. Since there is little difference in expression of IgLONs on the surface of chick forebrain neurons at these two ages we suggest IgLONs alone are not the receptor on the responding forebrain neurons. A DIgLON heterodimeric recombinant protein DIgLON:CEPU-1-OBCAM-Fc also blocked neurite outgrowth from E8 chick forebrain neurons. However, when IgLONs were removed from the surface of these E8 neurons they no longer responded to DIgLON:CEPU-1-OBCAM-Fc substrate, indicating that IgLONs form at least a component of the neuronal cell receptor complex involved in this inhibition of neurite outgrowth. Inhibitors pertussis toxin and Y27632 reversed the inhibition of neurite outgrowth on a DIgLON:CEPU-1-OBCAM and DIgLON:CEPU-1-LAMP substrate. This suggests the involvement of a G-protein coupled receptor and activation of Rho A. In summary we provide evidence that DIgLON:CEPU-1-OBCAM and DIgLON:CEPU-1-LAMP complexes regulate initiation of neurite outgrowth on forebrain neurons via an IgLON-containing receptor complex.
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PMID:DIgLONs inhibit initiation of neurite outgrowth from forebrain neurons via an IgLON-containing receptor complex. 2116 20

Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.
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PMID:PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis. 2351 82

Cell competition is a quality control mechanism that eliminates unfit cells. How cells compete is poorly understood, but it is generally accepted that molecular exchange between cells signals elimination of unfit cells. Here we report an orthogonal mechanism of cell competition, whereby cells compete through mechanical insults. We show that MDCK cells silenced for the polarity gene scribble (scrib(KD)) are hypersensitive to compaction, that interaction with wild-type cells causes their compaction and that crowding is sufficient for scrib(KD) cell elimination. Importantly, we show that elevation of the tumour suppressor p53 is necessary and sufficient for crowding hypersensitivity. Compaction, via activation of Rho-associated kinase (ROCK) and the stress kinase p38, leads to further p53 elevation, causing cell death. Thus, in addition to molecules, cells use mechanical means to compete. Given the involvement of p53, compaction hypersensitivity may be widespread among damaged cells and offers an additional route to eliminate unfit cells.
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PMID:Mechanical cell competition kills cells via induction of lethal p53 levels. 2710 13


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