R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells
- PMID: 10803462
- DOI: 10.1038/sj.onc.1203530
R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells
Abstract
The GTP-binding protein, R-Ras3/M-Ras, is a novel member of the Ras subfamily of GTPases which shows highest sequence similarity to the TC21 gene. R-Ras3 is highly expressed in both human and mouse brain and ectopic expression of a constitutively active mutant of R-Ras3 induces cellular transformation in NIH3T3 cells. To gain further insight into the normal cellular function of R-Ras3, we examined the ability of R-Ras3 in activating several known intracellular signaling cascades. We observed that R-Ras3 is a relatively weak activator of the mitogen-activated protein kinase/extracellular-signal-regulated kinases (MAPK/ERKs) when compared to the H-Ras oncogene. On the contrary, both R-Ras3 and H-Ras activated the Jun N-terminal kinase (JNK) to a similar extent. Under similar experimental conditions, R-Ras3 significantly stimulated one of the phosphatidylinositol 3-kinase (PI3-K) downstream substrates, Akt/PKB/RAC (Akt), which has been extensively implicated in mediating cell survival signaling. The activation of Akt by R-Ras3 was most likely to be PI3-K-dependent since this biochemical event was blocked by the pharmacological inhibitors, Wortmannin and LY294002, as well as by a dominant negative mutant of PI3-K. More importantly, R-Ras3 affinity-precipitated PI3-K from cell extracts in a GTP-dependent manner, and associated lipid kinase activity was readily detectable in R-Ras3 immune complexes. The biological significance of R-Ras3 in inducing Akt kinase activity is evidenced by the ability of an activated R-Ras3 to confer cell survival in the rat pheochromocytoma cell line, PC12. As expected, this biological activity of R-Ras3 was also abrogated by the addition of LY294002. Thus, R-Ras3 represents a novel G-protein which may play a role in cell survival of neural-derived cells.
Similar articles
-
R-Ras3/M-Ras induces neuronal differentiation of PC12 cells through cell-type-specific activation of the mitogen-activated protein kinase cascade.Mol Cell Biol. 2002 Aug;22(16):5946-61. doi: 10.1128/MCB.22.16.5946-5961.2002. Mol Cell Biol. 2002. PMID: 12138204 Free PMC article.
-
Apigenin and LY294002 prolong EGF-stimulated ERK1/2 activation in PC12 cells but are unable to induce full differentiation.FEBS Lett. 2002 Jan 16;510(3):149-53. doi: 10.1016/s0014-5793(01)03252-5. FEBS Lett. 2002. PMID: 11801244
-
Rit, a non-lipid-modified Ras-related protein, transforms NIH3T3 cells without activating the ERK, JNK, p38 MAPK or PI3K/Akt pathways.Oncogene. 2000 Sep 28;19(41):4685-94. doi: 10.1038/sj.onc.1203836. Oncogene. 2000. PMID: 11032018
-
Rit subfamily small GTPases: regulators in neuronal differentiation and survival.Cell Signal. 2013 Oct;25(10):2060-8. doi: 10.1016/j.cellsig.2013.06.002. Epub 2013 Jun 11. Cell Signal. 2013. PMID: 23770287 Free PMC article. Review.
-
A target for phosphoinositide 3-kinase: Akt/PKB.Trends Biochem Sci. 1995 Nov;20(11):441-2. doi: 10.1016/s0968-0004(00)89097-0. Trends Biochem Sci. 1995. PMID: 8578585 Review. No abstract available.
Cited by
-
Absence of M-Ras modulates social behavior in mice.BMC Neurosci. 2015 Oct 21;16:68. doi: 10.1186/s12868-015-0209-8. BMC Neurosci. 2015. PMID: 26490652 Free PMC article.
-
Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell.Int J Clin Exp Pathol. 2013 Nov 15;6(12):2745-56. eCollection 2013. Int J Clin Exp Pathol. 2013. PMID: 24294361 Free PMC article.
-
Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma.Gastroenterology. 2008 May;134(5):1521-31. doi: 10.1053/j.gastro.2008.02.015. Epub 2008 Feb 13. Gastroenterology. 2008. PMID: 18471523 Free PMC article.
-
Inactivation of MAP kinase signalling in Myc transformed cells and rescue by LiCl inhibition of GSK3.Mol Cancer. 2005 Apr 5;4(1):13. doi: 10.1186/1476-4598-4-13. Mol Cancer. 2005. Retraction in: Mol Cancer. 2005 May 06;4(1):17. doi: 10.1186/1476-4598-4-17. PMID: 15811177 Free PMC article. Retracted.
-
Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis.J Cell Biochem. 2011 Feb;112(2):463-75. doi: 10.1002/jcb.22934. J Cell Biochem. 2011. PMID: 21268068 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous