Disease relevance of RASSF5

• NORE1B and RASSF3 were not methylated in gliomas, while NORE1A and RASSF5/AD037 demonstrated methylation in glioma cell lines but not in primary tumors [1].
• This gene is silenced and frequently inactivated by promoter region hypermethylation in many adult and childhood cancers, including lung, breast, kidney, gastric, bladder, neuroblastoma, medulloblastoma, gliomas and it has homology to a mammalian Ras effector (i.e., Nore1) [2].
• The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas [3].
• Therefore, we investigated the effects of UCFI-C on cell growth, prenylation of cellular proteins including ras and Rapl, MAP kinase activity, activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and synthesis of cholesterol in a ras-activated human hepatoma cell line, Hep G2 [4].
• Finally, we discuss the possible role of the NORE motif in relation to neuroendocrine lung tumor formation, and in particular the development of small cell lung cancer [5].

High impact information on RASSF5

• Here we show that a novel isoform of Rapl GTPase-activating protein, called rap1GAPII, binds specifically to the alpha-subunits of the G(i) family of heterotrimeric G-proteins [6].
• Our study demonstrates a previously unknown function for Mst1 of relaying the Rap1-RAPL signal to induce cell polarity and adhesion of lymphocytes [7].
• Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion [7].
• RAPL regulated the localization and kinase activity of Mst1. 'Knockdown' of the gene encoding Mst1 demonstrated its requirement for the induction of both a polarized morphology and integrin LFA-1 clustering and adhesion triggered by chemokines and T cell receptor ligation [7].
• Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes [8].

Chemical compound and disease context of RASSF5

• There were no changes in hematological parameters nore in the activity of malate and lactate dehydrogenases during normoxia and hypoxia, which suggest that these adaptive mechanisms may not be involved during hypoxia [9].

Biological context of RASSF5

• In addition, our data suggest that the nuclear localization of RASSF5 is critical for its cell growth control activity [10].
• Overexpression of constitutively active Ki-RasG12V promotes apoptosis in a variety of cell lines; Ha-RasG12V is a much less potent proapoptotic agent; however, a Ha-RasG12V effector loop mutant (E37G) that binds NORE, but not Raf or PI 3-kinase, exhibits proapoptotic efficacy approaching that of Ki-RasG12V [11].
• However, contrary to RASSF1A, gene silencing by methylation of the CpG islands at which the two NORE1 transcripts initiate is not a common event in human primary tumors [12].
• RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1 [12].
• In addition, disconnection of Rap1 and RAPL by expression of a RAPL mutant also perturbed wound healing [8].

Anatomical context of RASSF5

• Time lapse imaging of microtubules marked by enhanced green fluorescent protein-RAPL showed the directional growth of microtubules toward the leading edge of the migrating cells [8].
• Collectively, the locally activated Rap1 and its association with RAPL controls the directional migration of vascular endothelial cells [8].
• Thus, Nore1 suppresses the growth of some tumor cell lines through as yet unidentified effectors, independent of Ras-like proteins or MST1/2 [13].
• Transfection of these cells with an expression plasmid encoding PLC-gamma1 restored Rap1 activation by the TCR and the ability to adhere to ICAM-1, accompanied by polarized LFA-1 surface clustering colocalized with regulator of adhesion and polarization enriched in lymphoid tissues (RAPL) [14].
• Targeted deletion of RAPL in mice has demonstrated multiple indispensable roles for this protein in lymphocyte and dendritic cell trafficking critical for immunosurveillance [15].

Associations of RASSF5 with chemical compounds

• Thus, it is suggested that, in the presence of insulin resistance, the responsiveness of B-cells will determine whether the glucose tolerance will be nore homeostasis in other conditions associated with glucose intolerance, the metabolic basis of which is undefined [16].
• The guanine exchange factor C3G was found to be associated with CrkL at similar levels before and after RA treatment, but Rapl activation downstream of C3G was not inducible by RA [17].
• 2-Deoxy-D-glucose showed neither net reabsorption nore secretion [18].

Physical interactions of RASSF5

• The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 [19].

Other interactions of RASSF5

• NORE is homologous to the putative tumor suppressor RASSF1 and to the Caenorhabditis elegans polypeptide T24F1 [11].
• However, our results demonstrate that the epigenetic alteration of NORE1A is confined to lung tumors with a wild-type K-ras: 88% (15 of 17) of the tumors with NORE1 hypermethylation did not harbor a K-ras mutation (P=0.008, Fisher's exact test) [20].
• We review the role and mechanism of specific effectors in regulating the antiapoptotic (Raf, phosphatidylinositol 3-kinase and Tiam1) and apoptotic (Nore1 and RASSF1) actions of oncogenic Ras, and discuss the possibility that the effector actions of p120RasGAP make a significant contribution to Ras regulation of apoptotic events [21].
• However, TCDD did not selectively alter LFA-1 or Rapl expression in T-cell subsets [22].
• FNBP2 gene was linked to IKBKE and NORE1 genes on human chromosome 1q32 [23].

References