Ferdowsi University of Mashhad

Document Type : Review / Mini-Review

Author

Stem Cell Biology and Regenerative Medicine, Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

Abstract

     Small GTPases of RAS act as central regulators of intracellular signal transduction and translate external stimuli to the various cellular responses. Embryonic stem cell expressed RAS (ERAS) is a member of the RAS family that is specifically expressed in undifferentiated mouse embryonic stem cells, hepatic stellate cells and diverse human tumors, such as gastric, breast, brain, pancreatic, and colorectal tumors. Although ERAS belongs to GTPase family, it is an inefficient enzyme to hydrolyze GTP to GDP. Therefore, it remains mainly in its GTP-bound active form and contributes to sustained signal transduction. In comparison with classical members (HRAS, NRAS and KRAS4B), ERAS is known as a unique member, due to its temporal expression, remarkable amino acid sequence deviations and functional differences. Notably, ERAS has been recently proposed as a potential marker for drug resistance in several human tumors. In this minireview, I compare in great detail the biochemical properties of ERAS with conventional members of the RAS family, and discuss the main ERAS function in the control of the PI3K-AKT-mTORC survival pathway. Targeting this pathway may sensitize ERAS expressing cell populations to chemotherapy.

Keywords

Ahmadian M. R., Stege P., Scheffzek K. and Wittinghofer A. (1997) Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras. Nature Structural Biology 4:9, 686-689.
Alessi D. R., James S. R., Downes C. P., Holmes A. B., Gaffney P. R., Reese C. B. and et al. (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current Biology 7:261-269.
Andjelkovic M., Alessi D. R., Meier R., Fernandez A., Lamb N. J., Frech M. and et al. (1997) Role of translocation in the activation and function of protein kinase B. Journal of  Biological Chemistry 272:50, 31515-31524.
Avruch J., Long X., Lin Y., Ortiz-Vega S., Rapley J., Papageorgiou A. and et al. (2009) Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor1. Biochemical Society Transactions 37:1, 223-226.
Frias M. A., Thoreen C. C., Jaffe J. D., Schroder W., Sculley T., Carr S. A. and et al. (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Current Biology 16:18, 1865-1870.
Fritsch R., de Krijger I., Fritsch K., George R., Reason B., Kumar Madhu S. and et al. (2013) RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms. Cell 153:5, 1050-1063.
Fritsch R. and Downward J. (2013) SnapShot: Class I PI3K Isoform Signaling. Cell 154:4, 940-940.
Garcia-Martinez J. M. and Alessi D. R. (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochemistry Journal 416:3, 375-385.
Gentilella A., Kozma S. C. and Thomas G. (2015) A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1849:7, 812-820.
Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S., and et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:2, 177-189.
Hara K., Yonezawa K., Kozlowski M. T., Sugimoto T., Andrabi K., Weng Q. P., and et al. (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR.  Journal of Biological Chemistry, 272:42, 26457-26463.
Hers I., Vincent E. E. and Tavaré J. M. (2011) Akt signalling in health and disease. Cellular signalling, 23:10, 1515-1527.
Huang J. and Manning B. D. (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochemical Journal, 412:2, 179-190.
Iadevaia V., Huo Y., Zhang Z., Foster L. J. and Proud C. G. (2012) Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis. Biochemical Society Transactions, 40:1, 168-172.
Ikenoue T., Inoki K., Yang Q., Zhou X. and Guan K. L. (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. The EMBO journal, 27:14,1919-1931.
Inoki K., Li Y., Xu T. and Guan K. L. (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & development, 17:15, 1829-1834.
Inoki K., Li Y., Zhu T., Wu J. and Guan K. L. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature cell biology, 4:9, 648-657.
Jacinto E., Loewith R., Schmidt A., Lin S., Ruegg M. A., Hall A. and et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature cell biology, 6:11, 1122-1128.
Jean S. and Kiger A. A. (2014) Classes of phosphoinositide 3-kinases at a glance. Journal of cell science, 127:5, 923-928.
Kim J. E. and Chen J. (2004) regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53:11, 2748-2756.
Kok K., Geering B. and Vanhaesebroeck B. (2009) Regulation of phosphoinositide 3-kinase expression in health and disease. Trends in biochemical sciences, 34:3, 115-127.
Liu P., Gan W., Inuzuka H., Lazorchak A. S., Gao D., Arojo O., and et al. (2013) Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nature cell biology, 15:11, 1340-1350.
Liu P., Guo J., Gan W. and Wei W. (2014) Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity. Protein & cell, 5:3, 171-177.
Loewith R., Jacinto E., Wullschleger S., Lorberg A., Crespo J. L., Bonenfant D., and et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular cell, 10:3,  457-468.
Ma X. M. and Blenis J. (2009) Molecular mechanisms of mTOR-mediated translational control. Nature reviews Molecular cell biology, 10:5, 307-318.
Ma X. M., Yoon S. O., Richardson C. J., Julich K. and Blenis J. (2008) SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133:2, 303-313.
Nakhaei-Rad S., Haghighi F., Nouri P., Rezaei Adariani S., Lissy J., Kazemein Jasemi N. S., and et al. (2018) Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms. Critical reviews in biochemistry and molecular biology, 53:2, 130-156.
Nakhaei-Rad S., Nakhaeizadeh H., Götze S., Kordes C., Sawitza I., Hoffmann M. J., and et al. (2016) The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells. Journal of Biological Chemistry, 291:16, 8399-8413.
Nakhaei-Rad S., Nakhaeizadeh H., Kordes C., Cirstea I. C., Schmick M., Dvorsky R., and et al.  (2015) The Function of Embryonic Stem Cell-expressed RAS (E-RAS), a Unique RAS Family Member, Correlates with Its Additional Motifs and Its Structural Properties. Journal of Biological Chemistry, 290:25, 15892-15903.
Nakhaeizadeh H., Amin E., Nakhaei-Rad S., Dvorsky R. and Ahmadian M. R. (2016) The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions. PLoS One 11:12, e0167145.
Pearce L. R., Huang X., Boudeau J., Pawlowski R., Wullschleger S., Deak M., and et al. (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochemical Journal, 405:3, 513-522.
Pearce L. R., Komander D. and Alessi D. R. (2010) The nuts and bolts of AGC protein kinases. Nature reviews Molecular cell biology, 11:1, 9-22.
Peterson T. R., Laplante M., Thoreen C. C., Sancak Y., Kang S. A., Kuehl W. M., and et al. (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:5, 873-886.
Porstmann T., Santos C. R., Griffiths B., Cully M., Wu M., Leevers S., and et al. (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell metabolism, 8:3, 224-236.
Pylayeva-Gupta Y., Grabocka E. and Bar-Sagi D. (2011) RAS oncogenes: weaving a tumorigenic web. Nature Reviews Cancer, 11:11, 761-774.
Sancak Y., Peterson T. R., Shaul Y. D., Lindquist R. A., Thoreen C. C., Bar-Peled L. and et al. (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:5882, 1496-1501.
Sancak Y., Thoreen C. C., Peterson T. R., Lindquist R. A., Kang S. A., Spooner E., and et al. (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Molecular cell, 25:6, 903-915.
Sarbassov D. D. (2005) Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science 307:5712, 1098-1101.
Sarbassov D. D., Ali S. M., Kim D. H., Guertin D. A., Latek R. R., Erdjument-Bromage H., and et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current biology, 14:14, 1296-1302.
Scheffzek K., Ahmadian M. R., Kabsch W., Wiesmuller L., Lautwein A., Schmitz F. and et al. (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:5324, 333-338.
Su B. and Jacinto E. (2011) Mammalian TOR signaling to the AGC kinases. Critical reviews in biochemistry and molecular biology, 46:6, 527-547.
Takahashi K., Mitsui K. and Yamanaka S. (2003) Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423:6939, 541-545.
Tee A. R., Manning B. D., Roux P. P., Cantley L. C. and Blenis J. (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current biology, 13:15, 1259-1268.
Vadas O., Burke J. E., Zhang X., Berndt A. and Williams R. L. (2011) Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Science Signaling 4:195, re2.
Vanhaesebroeck B., Ali K., Bilancio A., Geering B. and Foukas L. C. (2005) Signalling by PI3K isoforms: insights from gene-targeted mice. Trends in biochemical sciences, 30:4, 194-204.
Vanhaesebroeck B., Leevers S. J., Ahmadi K., Timms J., Katso R., Driscoll P. C., and et al.  (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annual review of biochemistry, 70:1, 535-602.
Vanhaesebroeck B., Vogt P. K. and Rommel C. (2010) PI3K: from the bench to the clinic and back. Current Topics in Microbiology and Immunology 347:1-19.
Vanhaesebroeck B., Vogt P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 347. Springer, Berlin, Heidelberg.
Wang X., Li W., Williams M., Terada N., Alessi D. R. and Proud C. G. (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. The EMBO journal, 20:16, 4370-4379.
Xie J. and Proud C. G. (2013) Crosstalk between mTOR complexes. Nature cell biology, 15:11, 1263-1265.
Yang Q., Inoki K., Ikenoue T. and Guan K. L. (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes & development, 20:20, 2820-2832.
Yashiro M., Yasuda K., Nishii T., Kaizaki R., Sawada T., Ohira M. and et al. (2009) Epigenetic regulation of the embryonic oncogene ERas in gastric cancer cells. International journal of oncology, 35:5, 997-1003.
Yasuda K., Yashiro M., Sawada T., Ohira M. and Hirakawa K. (2007) ERas oncogene expression and epigenetic regulation by histone acetylation in human cancer cells. Anticancer Research 27:6b, 4071-4075.
Yu L., McPhee C. K., Zheng L., Mardones G. A., Rong Y., Peng J., and et al. (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465: 7300, 942-946.
Zinzalla V., Stracka D., Oppliger W. and Hall Michael N. (2011) Activation of mTORC2 by Association with the Ribosome. Cell 144:5, 757-768.
Zoncu R., Efeyan A. and Sabatini D. M. (2010) mTOR: from growth signal integration to cancer, diabetes and ageing. Nature reviews Molecular cell biology, 12:1, 21-35.