Skip to main content

Advertisement

SpringerLink
Log in

The role of ral signaling and post translational modifications (PTMs) of Ras in cancer

  • Review Article
  • Published:
Genome Instability & Disease Aims and scope Submit manuscript

Abstract

Mutation in RAS gene is one of the most common genetic alterations, which seems to be seen in one third of human cancers. Ras, as a molecular switch, has been considered in wide variety of signaling pathways such as cell division and apoptosis. Ras proteins have a binary function to transmit different extracellular messages into intracellular signaling network. It has been proved that Ras proteins associate with different plasma membranes. Although all Ras isoforms have been found at plasma membrane, H-Ras and N-Ras are located in Golgi, and K-Ras at ER and mitochondria outer membrane. There have been a lot of efforts to inhibit Ras signaling that can be a pivotal approach to treat Ras-induced tumors. Effect of RalA and RalB on the growth of embryonal tumors, at downstream region of Ras, has been studied in a number of studies, which showed that inhibition of these signaling pathways can provide a strong therapeutic approach to cancer. Also, post translational modifications (PTMs) in proteins interfere extremely with cell signaling pathways in cells that can react to external signals. In this review, the role of Ral signaling in cancer and PTM of Ras proteins has been reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Ahearn, I. M., Haigis, K., Bar-Sagi, D., & Philips, M. R. (2012). Regulating the regulator: Post-translational modification of RAS. Nature Reviews Molecular Cell Biology, 13(1), 39–51.

    CAS  Google Scholar 

  • Ahearn, I., Zhou, M., & Philips, M. R. (2018). Posttranslational modifications of RAS proteins. Cold Spring Harbor Perspectives in Medicine, 8(11), a031484.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alvarez-Moya, B., Lopez-Alcala, C., Drosten, M., Bachs, O., & Agell, N. (2010). K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function. Oncogene, 29(44), 5911–5922.

    CAS  PubMed  Google Scholar 

  • Apolloni, A., Prior, I. A., Lindsay, M., Parton, R. G., & Hancock, J. F. (2000). H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Molecular and Cellular Biology, 20(7), 2475–2487.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aranda, E., Lopez-Pedrera, C., De La Haba-Rodriguez, R. J., & Rodriguez-Ariza, A. (2012). Nitric oxide and cancer: The emerging role of S-nitrosylation. Current Molecular Medicine, 12(1), 50–67.

    CAS  PubMed  Google Scholar 

  • Awasthi, S., Cheng, J., Singhal, S. S., Saini, M. K., Pandya, U., Pikula, S., Awasthi, Y. C., et al. (2000). Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry, 39(31), 9327–9334.

    CAS  PubMed  Google Scholar 

  • Baker, R., Wilkerson, E. M., Sumita, K., Isom, D. G., Sasaki, A. T., Dohlman, H. G., & Campbell, S. L. (2013). Differences in the regulation of K-Ras and H-Ras isoforms by monoubiquitination. Journal of Biological Chemistry, 288(52), 36856–36862.

    CAS  Google Scholar 

  • Ballester, R., Furth, M., & Rosen, O. (1987). Phorbol ester-and protein kinase C-mediated phosphorylation of the cellular Kirsten ras gene product. Journal of Biological Chemistry, 262(6), 2688–2695.

    CAS  Google Scholar 

  • Beel, S., Kolloch, L., Apken, L. H., Jürgens, L., Bolle, A., Sudhof, N., Steinestel, K., et al. (2020). κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis. Nature Communications, 11(1), 1–16.

    Google Scholar 

  • Bergo, M. O., Ambroziak, P., Gregory, C., George, A., Otto, J. C., Kim, E., Young, S. G., et al. (2002). Absence of the CAAX endoprotease Rce1: Effects on cell growth and transformation. Molecular and Cellular Biology, 22(1), 171–181.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bergo, M. O., Gavino, B. J., Hong, C., Beigneux, A. P., McMahon, M., Casey, P. J., & Young, S. G. (2004). Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. The Journal of Clinical Investigation, 113(4), 539–550.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Biondini, M., Duclos, G., Meyer-Schaller, N., Silberzan, P., Camonis, J., & Parrini, M. C. (2015). RalB regulates contractility-driven cancer dissemination upon TGFβ stimulation via the RhoGEF GEF-H1. Scientific Reports, 5(1), 1–14.

    Google Scholar 

  • Bivona, T. G., De Castro, I. P., Ahearn, I. M., Grana, T. M., Chiu, V. K., Lockyer, P. J., Philips, M. R., et al. (2003). Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1. Nature, 424(6949), 694–698.

    CAS  PubMed  Google Scholar 

  • Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Saba, S. G., et al. (2006). PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Molecular Cell, 21(4), 481–493.

    CAS  PubMed  Google Scholar 

  • Bodemann, B. O., Orvedahl, A., Cheng, T., Ram, R. R., Ou, Y.-H., Formstecher, E., Balakireva, M., et al. (2011). RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell, 144(2), 253–267.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bodemann, B. O., & White, M. A. (2008). Ral GTPases and cancer: Linchpin support of the tumorigenic platform. Nature Reviews Cancer, 8(2), 133–140.

    CAS  PubMed  Google Scholar 

  • Caloca, M. J., Zugaza, J. L., & Bustelo, X. R. (2003). Exchange factors of the RasGRP family mediate Ras activation in the Golgi. Journal of Biological Chemistry, 278(35), 33465–33473.

    CAS  Google Scholar 

  • Camonis, J. H., & White, M. A. (2005). Ral GTPases: Corrupting the exocyst in cancer cells. Trends in Cell Biology, 15(6), 327–332.

    CAS  PubMed  Google Scholar 

  • Cantor, S. B., Urano, T., & Feig, L. A. (1995). Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Molecular and Cellular Biology, 15(8), 4578–4584.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cascone, I., Selimoglu, R., Ozdemir, C., Del Nery, E., Yeaman, C., White, M., & Camonis, J. (2008). Distinct roles of RalA and RalB in the progression of cytokinesis are supported by distinct RalGEFs. The EMBO Journal, 27(18), 2375–2387.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Casey, P. J., Solski, P. A., Der, C. J., & Buss, J. E. (1989). p21ras is modified by a farnesyl isoprenoid. Proceedings of the National Academy of Sciences, 86(21), 8323–8327.

    CAS  Google Scholar 

  • Chen, C. Y., & Faller, D. V. (1995). Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. Oncogene, 11(8), 1487–1498.

    CAS  PubMed  Google Scholar 

  • Chen, Q., Quan, C., Xie, B., Chen, L., Zhou, S., Toth, R., Horiuchi, H., et al. (2014). GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins. Cellular Signalling, 26(8), 1636–1648.

    CAS  PubMed  Google Scholar 

  • Chen, X.-W., Inoue, M., Hsu, S. C., & Saltiel, A. R. (2006). RalA-exocyst-dependent recycling endosome trafficking is required for the completion of cytokinesis. Journal of Biological Chemistry, 281(50), 38609–38616.

    CAS  Google Scholar 

  • Chen, X.-W., Leto, D., Chiang, S.-H., Wang, Q., & Saltiel, A. R. (2007). Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. Developmental Cell, 13(3), 391–404.

    CAS  PubMed  Google Scholar 

  • Chen, X.-W., Leto, D., Xiong, T., Yu, G., Cheng, A., Decker, S., & Saltiel, A. R. (2011). A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Molecular Biology of the Cell, 22(1), 141–152.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chien, Y., Kim, S., Bumeister, R., Loo, Y.-M., Kwon, S. W., Johnson, C. L., Gale, M., Jr., et al. (2006). RalB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell, 127(1), 157–170.

    CAS  PubMed  Google Scholar 

  • Chien, Y., & White, M. A. (2003). RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Reports, 4(8), 800–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu, V. K., Bivona, T., Hach, A., Sajous, J. B., Silletti, J., Wiener, H., Philips, M. R., et al. (2002). Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biology, 4(5), 343–350.

    CAS  PubMed  Google Scholar 

  • Choy, E., Chiu, V. K., Silletti, J., Feoktistov, M., Morimoto, T., Michaelson, D., Philips, M. R., et al. (1999). Endomembrane trafficking of ras: The CAAX motif targets proteins to the ER and Golgi. Cell, 98(1), 69–80.

    CAS  PubMed  Google Scholar 

  • Crespo, N. C., Ohkanda, J., Yen, T. J., Hamilton, A. D., & Sebti, S. D. M. (2001). The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. Journal of Biological Chemistry, 276(19), 16161–16167.

    CAS  Google Scholar 

  • de Bruyn, K. M., de Rooij, J., Wolthuis, R. M., Rehmann, H., Wesenbeek, J., Cool, R. H., Bos, J. L., et al. (2000). RalGEF2, a pleckstrin homology domain containing guanine nucleotide exchange factor for Ral. Journal of Biological Chemistry, 275(38), 29761–29766.

    Google Scholar 

  • de Gorter, D. J., Reijmers, R. M., Beuling, E. A., Naber, H. P., Kuil, A., Kersten, M. J., Spaargaren, M., et al. (2008). The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cells. Blood, the Journal of the American Society of Hematology, 111(7), 3364–3372.

    Google Scholar 

  • Dower, N. A., Stang, S. L., Bottorff, D. A., Ebinu, J. O., Dickie, P., Ostergaard, H. L., & Stone, J. C. (2000). RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nature Immunology, 1(4), 317–321.

    CAS  PubMed  Google Scholar 

  • Ebinu, J. O., Stang, S. L., Teixeira, C., Bottorff, D. A., Hooton, J., Blumberg, P. M., Stone, J. C., et al. (2000). RasGRP links T-cell receptor signaling to Ras. Blood, the Journal of the American Society of Hematology, 95(10), 3199–3203.

    CAS  Google Scholar 

  • Ehrhardt, A., Ehrhardt, G. R., Guo, X., & Schrader, J. W. (2002). Ras and relatives—job sharing and networking keep an old family together. Experimental Hematology, 30(10), 1089–1106.

    CAS  PubMed  Google Scholar 

  • Emkey, R., Freedman, S., & Feig, L. (1991). Characterization of a GTPase-activating protein for the Ras-related Ral protein. Journal of Biological Chemistry, 266(15), 9703–9706.

    CAS  Google Scholar 

  • Falsetti, S. C., Wang, D.-A., Peng, H., Carrico, D., Cox, A. D., Der, C. J., Sebti, S. M., et al. (2007). Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Molecular and Cellular Biology, 27(22), 8003–8014.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Farnsworth, C. C., Gelb, M. H., & Glomset, J. A. (1990). Identification of geranylgeranyl-modified proteins in HeLa cells. Science, 247(4940), 320–322.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Farnsworth, C. C., Wolda, S. L., Gelb, M. H., & Glomset, J. A. (1989). Human lamin B contains a farnesylated cysteine residue. Journal of Biological Chemistry, 264(34), 20422–20429.

    CAS  Google Scholar 

  • Fernández, R. M., Ruiz-Miró, M., Dolcet, X., Aldea, M., & Garí, E. (2011). Cyclin D1 interacts and collaborates with Ral GTPases enhancing cell detachment and motility. Oncogene, 30(16), 1936–1946.

    PubMed  Google Scholar 

  • Fruman, D. A., & Rommel, C. (2014). PI3K and cancer: Lessons, challenges and opportunities. Nature Reviews Drug Discovery, 13(2), 140–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fukai, S., Matern, H. T., Jagath, J. R., Scheller, R. H., & Brunger, A. T. (2003). Structural basis of the interaction between RalA and Sec5, a subunit of the sec6/8 complex. The EMBO Journal, 22(13), 3267–3278.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao, P., Liu, S., Yoshida, R., Shi, C., Yoshimachi, S., Sakata, N., Nakayama, H., et al. (2019). Ral GTPase activation by downregulation of RalGAP enhances oral squamous cell carcinoma progression. Journal of Dental Research, 98(9), 1011–1019.

    CAS  PubMed  Google Scholar 

  • Gentry, L. R., Martin, T. D., Reiner, D. J., & Der, C. J. (2014). Ral small GTPase signaling and oncogenesis: more than just 15 minutes of fame. Biochimica Et Biophysica Acta (BBA)-Molecular Cell Research, 1843(12), 2976–2988.

    CAS  Google Scholar 

  • Gentry, L. R., Nishimura, A., Cox, A. D., Martin, T. D., Tsygankov, D., Nishida, M., Der, C. J., et al. (2015). Divergent roles of CAAX motif-signaled posttranslational modifications in the regulation and subcellular localization of Ral GTPases. Journal of Biological Chemistry, 290(37), 22851–22861.

    CAS  Google Scholar 

  • Goldfinger, L. E., Ptak, C., Jeffery, E. D., Shabanowitz, J., Hunt, D. F., & Ginsberg, M. H. (2006). RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. The Journal of Cell Biology, 174(6), 877–888.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guin, S., Ru, Y., Wynes, M. W., Mishra, R., Lu, X., Owens, C., Kern, J. A., et al. (2013). Contributions of KRAS and RAL in non–small-cell lung cancer growth and progression. Journal of Thoracic Oncology, 8(12), 1492–1501.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Győrffy, B., Stelniec-Klotz, I., Sigler, C., Kasack, K., Redmer, T., Qian, Y., & Schäfer, R. (2015). Effects of RAL signal transduction in KRAS-and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer. Oncotarget, 6(15), 13334.

    PubMed  PubMed Central  Google Scholar 

  • Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999). Creation of human tumour cells with defined genetic elements. Nature, 400(6743), 464–468.

    CAS  PubMed  Google Scholar 

  • Halloran, M., Parakh, S., & Atkin, J. (2013). The role of s-nitrosylation and s-glutathionylation of protein disulphide isomerase in protein misfolding and neurodegeneration. International Journal of Cell Biology, 2013, 5.

    Google Scholar 

  • Hamada, M., Miki, T., Iwai, S., Shimizu, H., & Yura, Y. (2011). Involvement of RhoA and RalB in geranylgeranyltransferase I inhibitor-mediated inhibition of proliferation and migration of human oral squamous cell carcinoma cells. Cancer Chemotherapy and Pharmacology, 68(3), 559–569.

    CAS  PubMed  Google Scholar 

  • Han, K., Kim, M.-H., Seeburg, D., Seo, J., Verpelli, C., Han, S., Kim, K., et al. (2009). Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD. PLoS Biology, 7(9), e1000187.

    PubMed  PubMed Central  Google Scholar 

  • Hancock, J. F. (2003). Ras proteins: Different signals from different locations. Nature Reviews Molecular Cell Biology, 4(5), 373–385.

    CAS  PubMed  Google Scholar 

  • Hazelett, C. C., Sheff, D., & Yeaman, C. (2011). RalA and RalB differentially regulate development of epithelial tight junctions. Molecular Biology of the Cell, 22(24), 4787–4800.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hazelett, C. C., & Yeaman, C. (2012). Sec5 and Exo84 mediate distinct aspects of RalA-dependent cell polarization. PLoS ONE, 7(6), e39602.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heo, J., & Campbell, S. L. (2004). Mechanism of p21Ras S-nitrosylation and kinetics of nitric oxide-mediated guanine nucleotide exchange. Biochemistry, 43(8), 2314–2322.

    CAS  PubMed  Google Scholar 

  • Jeong, W.-J., Yoon, J., Park, J.-C., Lee, S.-H., Lee, S.-H., Kaduwal, S., Choi, K.-Y., et al. (2012). Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis. Science Signaling, 5(219), ra30–ra31.

    PubMed  Google Scholar 

  • Jin, R., Junutula, J. R., Matern, H. T., Ervin, K. E., Scheller, R. H., & Brunger, A. T. (2005). Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO Journal, 24(12), 2064–2074.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jullien-Flores, V., Dorseuil, O., Romero, F., Letourneur, F., Saragosti, S., Berger, R., Camonis, J. H., et al. (1995). Bridging Ral GTPase to Rho pathways: RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. Journal of Biological Chemistry, 270(38), 22473–22477.

    CAS  Google Scholar 

  • Jullien-Flores, V., Mahé, Y., Mirey, G., Leprince, C., Meunier-Bisceuil, B., Sorkin, A., & Camonis, J. H. (2000). RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: Involvement of the Ral pathway in receptor endocytosis. Journal of Cell Science, 113(16), 2837–2844.

    CAS  PubMed  Google Scholar 

  • Jura, N., Scotto-Lavino, E., Sobczyk, A., & Bar-Sagi, D. (2006). Differential modification of Ras proteins by ubiquitination. Molecular Cell, 21(5), 679–687.

    CAS  PubMed  Google Scholar 

  • Karin, M., & Hunter, T. (1995). Transcriptional control by protein phosphorylation: Signal transmission from the cell surface to the nucleus. Current Biology, 5(7), 747–757.

    CAS  PubMed  Google Scholar 

  • Kashatus, D. F. (2013). Ral GTPases in tumorigenesis: Emerging from the shadows. Experimental Cell Research, 319(15), 2337–2342.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kawato, M., Shirakawa, R., Kondo, H., Higashi, T., Ikeda, T., Okawa, K., Horiuchi, H., et al. (2008). Regulation of platelet dense granule secretion by the Ral GTPase-exocyst pathway. Journal of Biological Chemistry, 283(1), 166–174.

    CAS  Google Scholar 

  • Khawaja, H., Campbell, A., Roberts, J. Z., Javadi, A., O’Reilly, P., McArt, D., Bardelli, A., et al. (2020). RALB GTPase: A critical regulator of DR5 expression and TRAIL sensitivity in KRAS mutant colorectal cancer. Cell Death & Disease, 11(10), 1–18.

    Google Scholar 

  • Kikuchi, A., Demo, S. D., Ye, Z.-H., Chen, Y.-W., & Williams, L. T. (1994). ralGDS family members interact with the effector loop of ras p21. Molecular and Cellular Biology, 14(11), 7483–7491.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, E., Ambroziak, P., Otto, J. C., Taylor, B., Ashby, M., Shannon, K., Young, S. G., et al. (1999). Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. Journal of Biological Chemistry, 274(13), 8383–8390.

    CAS  Google Scholar 

  • Kim, S.-E., Yoon, J.-Y., Jeong, W.-J., Jeon, S.-H., Park, Y., Yoon, J.-B., Choi, K.-Y., et al. (2009). H-Ras is degraded by Wnt/β-catenin signaling via β-TrCP-mediated polyubiquitylation. Journal of Cell Science, 122(6), 842–848.

    CAS  PubMed  Google Scholar 

  • Kohl, N. E., Mosser, S. D., DeSolms, S. J., Giuliani, E. A., Pompliano, D. L., Graham, S. L., Gibbs, J. B., et al. (1993). Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science, 260(5116), 1934–1937.

    CAS  PubMed  Google Scholar 

  • Lander, H. M., Hajjar, D. P., Hempstead, B. L., Mirza, U. A., Chait, B. T., Campbell, S., & Quilliam, L. A. (1997). A molecular redox switch on p21ras: Structural basis for the nitric oxide-p21ras interaction. Journal of Biological Chemistry, 272(7), 4323–4326.

    CAS  Google Scholar 

  • Lander, H. M., Milbank, A. J., Tauras, J. M., Hajjar, D. P., Hempstead, B. L., Schwartz, G. D., Burk, S. C., et al. (1996). Redox regulation of cell signalling. Nature, 381(6581), 380–381.

    CAS  PubMed  Google Scholar 

  • Lerner, E. C., Qian, Y., Blaskovich, M. A., Fossum, R. D., Vogt, A., Sun, J., Sebti, S. M., et al. (1995). Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. Journal of Biological Chemistry, 270(45), 26802–26806.

    CAS  Google Scholar 

  • Leto, D., Uhm, M., Williams, A., Chen, X.-W., & Saltiel, A. R. (2013). Negative regulation of the RalGAP complex by 14-3-3. Journal of Biological Chemistry, 288(13), 9272–9283.

    CAS  Google Scholar 

  • Li, G., Han, L., Chou, T.-C., Fujita, Y., Arunachalam, L., Xu, A., Wang, L., et al. (2007). RalA and RalB function as the critical GTP sensors for GTP-dependent exocytosis. Journal of Neuroscience, 27(1), 190–202.

    PubMed  Google Scholar 

  • Lim, K.-H., Ancrile, B. B., Kashatus, D. F., & Counter, C. M. (2008). Tumour maintenance is mediated by eNOS. Nature, 452(7187), 646–649.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lim, K.-H., Brady, D. C., Kashatus, D. F., Ancrile, B. B., Der, C. J., Cox, A. D., & Counter, C. M. (2010). Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Molecular and Cellular Biology, 30(2), 508–523.

    CAS  PubMed  Google Scholar 

  • Lim, K.-H., O’Hayer, K., Adam, S. J., Kendall, S. D., Campbell, P. M., Der, C. J., & Counter, C. M. (2006). Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Current Biology, 16(24), 2385–2394.

    CAS  PubMed  Google Scholar 

  • Liu, M., Sjogren, A.-K.M., Karlsson, C., Ibrahim, M. X., Andersson, K. M., Olofsson, F. J., Chen, Z., et al. (2010). Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proceedings of the National Academy of Sciences, 107(14), 6471–6476.

    CAS  Google Scholar 

  • Ljubicic, S., Bezzi, P., Vitale, N., & Regazzi, R. (2009). The GTPase RalA regulates different steps of the secretory process in pancreatic β-cells. PLoS ONE, 4(11), e7770.

    PubMed  PubMed Central  Google Scholar 

  • Lobell, R. B., Liu, D., Buser, C. A., Davide, J. P., DePuy, E., Hamilton, K., Motzel, S. L., et al. (2002). Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl: Protein transferase and geranylgeranyl: Protein transferase type-I. Molecular Cancer Therapeutics, 1(9), 747–758.

    CAS  PubMed  Google Scholar 

  • Lu, J., Chan, L., Fiji, H. D., Dahl, R., Kwon, O., & Tamanoi, F. (2009). In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Molecular Cancer Therapeutics, 8(5), 1218–1226.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maehama, T., Tanaka, M., Nishina, H., Murakami, M., Kanaho, Y., & Hanada, K. (2008). RalA functions as an indispensable signal mediator for the nutrient-sensing system. Journal of Biological Chemistry, 283(50), 35053–35059.

    CAS  Google Scholar 

  • Male, H., Patel, V., Jacob, M. A., Borrego-Diaz, E., Wang, K., Young, D. A., O’Brien-Ladner, A., et al. (2012). Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer. Lung Cancer, 77(2), 252–259.

    PubMed  Google Scholar 

  • Marozkina, N. V., Wei, C., Yemen, S., Wallrabe, H., Nagji, A. S., Liu, L., Gaston, B., et al. (2012). S-nitrosoglutathione reductase in human lung cancer. American Journal of Respiratory Cell and Molecular Biology, 46(1), 63–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martegani, E., Ceriani, M., Tisi, R., & Berruti, G. (2002). Cloning and characterization of a new Ral-GEF expressed in mouse testis. Annals of the New York Academy of Sciences, 973(1), 135–137.

    CAS  PubMed  Google Scholar 

  • Martin, T. D., Chen, X.-W., Kaplan, R. E., Saltiel, A. R., Walker, C. L., Reiner, D. J., & Der, C. J. (2014). Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Molecular Cell, 53(2), 209–220.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin, T. D., & Der, C. J. (2012). Differential involvement of RalA and RalB in colorectal cancer. Small GTPases, 3(2), 126–130.

    PubMed  PubMed Central  Google Scholar 

  • Martin, T. D., Mitin, N., Cox, A. D., Yeh, J. J., & Der, C. J. (2012). Phosphorylation by protein kinase Cα regulates RalB small GTPase protein activation, subcellular localization, and effector utilization. Journal of Biological Chemistry, 287(18), 14827–14836.

    CAS  Google Scholar 

  • McLaughlin, S., & Aderem, A. (1995). The myristoyl-electrostatic switch: A modulator of reversible protein-membrane interactions. Trends in Biochemical Sciences, 20(7), 272–276.

    CAS  PubMed  Google Scholar 

  • Michaelson, D., Ali, W., Chiu, V. K., Bergo, M., Silletti, J., Wright, L., Philips, M., et al. (2005). Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases. Molecular Biology of the Cell, 16(4), 1606–1616.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moghadam, A. R., Patrad, E., Tafsiri, E., Peng, W., Fangman, B., Pluard, T. J., Ricke, B., et al. (2017). Ral signaling pathway in health and cancer. Cancer Medicine, 6(12), 2998–3013.

    PubMed  PubMed Central  Google Scholar 

  • Mollberg, N., Steinert, G., Aigner, M., Hamm, A., Lin, F.-J., Elbers, H., Koch, M., et al. (2012). Overexpression of RalBP1 in colorectal cancer is an independent predictor of poor survival and early tumor relapse. Cancer Biology & Therapy, 13(8), 694–700.

    CAS  Google Scholar 

  • Monteiro, H., Costa, P., Reis, A., & Stern, A. (2015). Nitric oxide: protein tyrosine phosphorylation and protein S-nitrosylation in cancer. Biomedical Journal, 38, 5.

    Google Scholar 

  • Moskalenko, S., Henry, D. O., Rosse, C., Mirey, G., Camonis, J. H., & White, M. A. (2002). The exocyst is a Ral effector complex. Nature Cell Biology, 4(1), 66–72.

    CAS  PubMed  Google Scholar 

  • Moskalenko, S., Tong, C., Rosse, C., Mirey, G., Formstecher, E., Daviet, L., White, M. A., et al. (2003). Ral GTPases regulate exocyst assembly through dual subunit interactions. Journal of Biological Chemistry, 278(51), 51743–51748.

    CAS  Google Scholar 

  • Nakashima, S., Morinaka, K., Koyama, S., Ikeda, M., Kishida, M., Okawa, K., Kikuchi, A., et al. (1999). Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. The EMBO Journal, 18(13), 3629–3642.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neel, N. F., Martin, T. D., Stratford, J. K., Zand, T. P., Reiner, D. J., & Der, C. J. (2011). The RalGEF-Ral effector signaling network: The road less traveled for anti-Ras drug discovery. Genes & Cancer, 2(3), 275–287.

    CAS  Google Scholar 

  • Neel, N. F., Rossman, K. L., Martin, T. D., Hayes, T. K., Yeh, J. J., & Der, C. J. (2012). The RalB small GTPase mediates formation of invadopodia through a GTPase-activating protein-independent function of the RalBP1/RLIP76 effector. Molecular and Cellular Biology, 32(8), 1374–1386.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neyraud, V., Aushev, V. N., Hatzoglou, A., Meunier, B., Cascone, I., & Camonis, J. (2012). RalA and RalB proteins are ubiquitinated GTPases, and ubiquitinated RalA increases lipid raft exposure at the plasma membrane. Journal of Biological Chemistry, 287(35), 29397–29405.

    CAS  Google Scholar 

  • Nishimura, A., & Linder, M. E. (2013). Identification of a novel prenyl and palmitoyl modification at the CaaX motif of Cdc42 that regulates RhoGDI binding. Molecular and Cellular Biology, 33(7), 1417–1429.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oeckinghaus, A., Postler, T. S., Rao, P., Schmitt, H., Schmitt, V., Grinberg-Bleyer, Y., Ghosh, S., et al. (2014). κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation. Cell Reports, 8(6), 1793–1807.

    CAS  PubMed  Google Scholar 

  • Oxford, G., Owens, C. R., Titus, B. J., Foreman, T. L., Herlevsen, M. C., Smith, S. C., & Theodorescu, D. (2005). RalA and RalB: Antagonistic relatives in cancer cell migration. Cancer Research, 65(16), 7111–7120.

    CAS  PubMed  Google Scholar 

  • Papini, D., Langemeyer, L., Abad, M. A., Kerr, A., Samejima, I., Eyers, P. A., Earnshaw, W. C., et al. (2015). TD-60 links RalA GTPase function to the CPC in mitosis. Nature Communications, 6(1), 1–12.

    Google Scholar 

  • Park, S.-H., & Weinberg, R. A. (1995). A putative effector of Ral has homology to Rho/Rac GTPase activating proteins. Oncogene, 11(11), 2349–2355.

    CAS  PubMed  Google Scholar 

  • Peterson, S. N., Trabalzini, L., Brtva, T. R., Fischer, T., Altschuler, D. L., Martelli, P., White, G. C., II., et al. (1996). Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1. Journal of Biological Chemistry, 271(47), 29903–29908.

    CAS  Google Scholar 

  • Rebhun, J. F., Chen, H., & Quilliam, L. A. (2000). Identification and characterization of a new family of guanine nucleotide exchange factors for the ras-related GTPase Ral. Journal of Biological Chemistry, 275(18), 13406–13410.

    CAS  Google Scholar 

  • Resh, M. D. (2013). Covalent lipid modifications of proteins. Current Biology, 23(10), R431–R435.

    CAS  PubMed  Google Scholar 

  • Rossé, C., L’Hoste, S., Offner, N., Picard, A., & Camonis, J. (2003). RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate epsin during the switch off of endocytosis in mitosis. Journal of Biological Chemistry, 278(33), 30597–30604.

    Google Scholar 

  • Sablina, A. A., Chen, W., Arroyo, J. D., Corral, L., Hector, M., Bulmer, S. E., Hahn, W. C., et al. (2007). The tumor suppressor PP2A Aβ regulates the RalA GTPase. Cell, 129(5), 969–982.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sasaki, A. T., Carracedo, A., Locasale, J. W., Anastasiou, D., Takeuchi, K., Kahoud, E. R., Cantley, L. C., et al. (2011). Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Science Signaling, 4(163), ra14–ra15.

    Google Scholar 

  • Seguin, L., Kato, S., Franovic, A., Camargo, M. F., Lesperance, J., Elliott, K. C., Husain, H., et al. (2014). An integrin β 3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology, 16(5), 457–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seibold, M., Stühmer, T., Kremer, N., Mottok, A., Scholz, C.-J., Schlosser, A., Barrio, S., et al. (2020). RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS. Haematologica, 105(9), 2316.

    CAS  PubMed  Google Scholar 

  • Shao, H., & Andres, D. A. (2000). A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. Journal of Biological Chemistry, 275(35), 26914–26924.

    CAS  Google Scholar 

  • Shipitsin, M., & Feig, L. A. (2004). RalA but not RalB enhances polarized delivery of membrane proteins to the basolateral surface of epithelial cells. Molecular and Cellular Biology, 24(13), 5746–5756.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shirakawa, R., Fukai, S., Kawato, M., Higashi, T., Kondo, H., Ikeda, T., Kimura, T., et al. (2009). Tuberous sclerosis tumor suppressor complex-like complexes act as GTPase-activating proteins for Ral GTPases. Journal of Biological Chemistry, 284(32), 21580–21588.

    CAS  Google Scholar 

  • Shirakawa, R., & Horiuchi, H. (2015). Ral GTPases: Crucial mediators of exocytosis and tumourigenesis. The Journal of Biochemistry, 157(5), 285–299.

    CAS  PubMed  Google Scholar 

  • Shukla, S., Allam, U. S., Ahsan, A., Chen, G., Krishnamurthy, P. M., Marsh, K., Schipper, M., et al. (2014). KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation. Neoplasia, 16(2), 115-W115.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sidhu, R. S., Clough, R. R., & Bhullar, R. P. (2003). Ca2+/calmodulin binds and dissociates K-RasB from membrane. Biochemical and Biophysical Research Communications, 304(4), 655–660.

    CAS  PubMed  Google Scholar 

  • Siegel-Lakhai, W., Crul, M., Zhang, S., Sparidans, R., Pluim, D., Howes, A., Schellens, J., et al. (2005). Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra®, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours. British Journal of Cancer, 93(11), 1222–1229.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Simicek, M., Lievens, S., Laga, M., Guzenko, D., Aushev, V. N., Kalev, P., Tavernier, J., et al. (2013). The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. Nature Cell Biology, 15(10), 1220–1230.

    CAS  PubMed  Google Scholar 

  • Sjogren, A.-K.M., Andersson, K. M., Liu, M., Cutts, B. A., Karlsson, C., Wahlstrom, A. M., Tarkowski, A., et al. (2007). GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer. The Journal of Clinical Investigation, 117(5), 1294–1304.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song, X., Hua, L., Xu, Y., Fang, Z., Wang, Y., Gao, J., Yu, R., et al. (2015). Involvement of RalB in the effect of geranylgeranyltransferase I on glioma cell migration and invasion. Clinical and Translational Oncology, 17(6), 477–485.

    CAS  PubMed  Google Scholar 

  • Sparano, J. A., Moulder, S., Kazi, A., Coppola, D., Negassa, A., Vahdat, L., Munster, P., et al. (2009). Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clinical Cancer Research, 15(8), 2942–2948.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sparano, J. A., Moulder, S., Kazi, A., Vahdat, L., Li, T., Pellegrino, C., Hoschander, S., et al. (2006). Targeted inhibition of farnesyltransferase in locally advanced breast cancer: A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. Journal of Clinical Oncology, 24(19), 3013–3018.

    CAS  PubMed  Google Scholar 

  • Sugihara, K., Asano, S., Tanaka, K., Iwamatsu, A., Okawa, K., & Ohta, Y. (2002). The exocyst complex binds the small GTPase RalA to mediate filopodia formation. Nature Cell Biology, 4(1), 73–78.

    CAS  PubMed  Google Scholar 

  • Sun, J., Qian, Y., Hamilton, A. D., & Sebti, S. M. (1995). Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Research, 55(19), 4243–4247.

    CAS  PubMed  Google Scholar 

  • Switzer, C. H., Cheng, R. Y., Ridnour, L. A., Glynn, S. A., Ambs, S., & Wink, D. A. (2012). Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast Cancer Research, 14(5), 1–13.

    Google Scholar 

  • Tang, C.-H., Wei, W., & Liu, L. (2012). Regulation of DNA repair by S-nitrosylation. Biochimica Et Biophysica Acta (BBA)-General Subjects, 1820(6), 730–735.

    CAS  Google Scholar 

  • Urano, T., Emkey, R., & Feig, L. A. (1996). Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. The EMBO Journal, 15(4), 810–816.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vigil, D., Martin, T. D., Williams, F., Yeh, J. J., Campbell, S. L., & Der, C. J. (2010). Aberrant overexpression of the Rgl2 Ral small GTPase-specific guanine nucleotide exchange factor promotes pancreatic cancer growth through Ral-dependent and Ral-independent mechanisms. Journal of Biological Chemistry, 285(45), 34729–34740.

    CAS  Google Scholar 

  • Wahlstrom, A. M., Cutts, B. A., Liu, M., Lindskog, A., Karlsson, C., Sjogren, A.-K.M., Bergo, M. O., et al. (2008). Inactivating Icmt ameliorates K-RAS–induced myeloproliferative disease. Blood, the Journal of the American Society of Hematology, 112(4), 1357–1365.

    CAS  Google Scholar 

  • Wang, C., Yuan, P., Xu, B., Yuan, L., Yang, H., & Liu, X. (2015). RLIP76 expression as a prognostic marker of breast cancer. European Review for Medical and Pharmacological Sciences, 19(11), 2105–2111.

    PubMed  Google Scholar 

  • Wang, H., Owens, C., Chandra, N., Conaway, M. R., Brautigan, D. L., & Theodorescu, D. (2010). Phosphorylation of RalB is important for bladder cancer cell growth and metastasis. Cancer Research, 70(21), 8760–8769.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, M., Hossain, M., Tan, W., Coolman, B., Zhou, J., Liu, S., & Casey, P. (2010). Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene, 29(35), 4959–4970.

    CAS  PubMed  Google Scholar 

  • Wang, Q., Wang, J.-Y., Zhang, X.-P., Lv, Z.-W., Fu, D., Lu, Y.-C., Chen, J.-X., et al. (2013). RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis. Carcinogenesis, 34(4), 916–926.

    CAS  PubMed  Google Scholar 

  • White, M. A., Vale, T., Camonis, J. H., Schaefer, E., & Wigler, M. H. (1996). A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. Journal of Biological Chemistry, 271(28), 16439–16442.

    CAS  Google Scholar 

  • Whyte, D. B., Kirschmeier, P., Hockenberry, T. N., Nunez-Oliva, I., James, L., Catino, J. J., Pai, J.-K., et al. (1997). K-and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. Journal of Biological Chemistry, 272(22), 14459–14464.

    CAS  Google Scholar 

  • Williams, J. G., Pappu, K., & Campbell, S. L. (2003). Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proceedings of the National Academy of Sciences, 100(11), 6376–6381.

    CAS  Google Scholar 

  • Willumsen, B. M., Christensen, A., Hubbert, N. L., Papageorge, A. G., & Lowy, D. R. (1984). The p21 ras C-terminus is required for transformation and membrane association. Nature, 310(5978), 583–586.

    CAS  PubMed  Google Scholar 

  • Winter-Vann, A. M., Kamen, B. A., Bergo, M. O., Young, S. G., Melnyk, S., James, S. J., & Casey, P. J. (2003). Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate. Proceedings of the National Academy of Sciences, 100(11), 6529–6534.

    CAS  Google Scholar 

  • Wolda, S. L., & Glomset, J. (1988). Evidence for modification of lamin B by a product of mevalonic acid. Journal of Biological Chemistry, 263(13), 5997–6000.

    CAS  Google Scholar 

  • Wu, Z., Owens, C., Chandra, N., Popovic, K., Conaway, M., & Theodorescu, D. (2010). RalBP1 is necessary for metastasis of human cancer cell lines. Neoplasia, 12(12), 1003–1012.

    PubMed  Google Scholar 

  • Xia, S., Forman, L. W., & Faller, D. V. (2007). Protein kinase Cδ is required for survival of cells expressing activated p21RAS. Journal of Biological Chemistry, 282(18), 13199–13210.

    CAS  Google Scholar 

  • Xu, L., Lubkov, V., Taylor, L. J., & Bar-Sagi, D. (2010). Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Current Biology, 20(15), 1372–1377.

    CAS  PubMed  Google Scholar 

  • Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Wysoczynski, C. L., et al. (2014). Discovery and characterization of small molecules that target the GTPase Ral. Nature, 515(7527), 443–447.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yan, C., & Theodorescu, D. (2018). RAL GTPases: Biology and potential as therapeutic targets in cancer. Pharmacological Reviews, 70(1), 1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yan, H., Jahanshahi, M., Horvath, E. A., Liu, H.-Y., & Pfleger, C. M. (2010). Rabex-5 ubiquitin ligase activity restricts Ras signaling to establish pathway homeostasis in Drosophila. Current Biology, 20(15), 1378–1382.

    CAS  PubMed  Google Scholar 

  • Yang, M. H., Laurent, G., Bause, A. S., Spang, R., German, N., Haigis, M. C., & Haigis, K. M. (2013). HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Molecular Cancer Research, 11(9), 1072–1077.

    CAS  PubMed  Google Scholar 

  • Yang, M. H., Nickerson, S., Kim, E. T., Liot, C., Laurent, G., Spang, R., Bar-Sagi, D., et al. (2012). Regulation of RAS oncogenicity by acetylation. Proceedings of the National Academy of Sciences, 109(27), 10843–10848.

    CAS  Google Scholar 

  • Yang, Q., Lang, C., Wu, Z., Dai, Y., He, S., Guo, W., Peng, X., et al. (2019). MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway. Journal of Experimental & Clinical Cancer Research, 38(1), 1–17.

    Google Scholar 

  • Zago, G., Veith, I., Singh, M. K., Fuhrmann, L., De Beco, S., Remorino, A., Brandon, N., et al. (2018). RalB directly triggers invasion downstream Ras by mobilizing the Wave complex. eLife, 7, e4074.

    Google Scholar 

  • Zhu, Z., Aref, A. R., Cohoon, T. J., Barbie, T. U., Imamura, Y., Yang, S., Thai, T. C., et al. (2014). Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discovery, 4(4), 452–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zinatizadeh, M. R., Miri, S. R., Zarandi, P. K., Chalbatani, G. M., Raposo, C., Mirzaei, H. R., Mahmoodzadeh, H., et al. (2021). The Hippo Tumor Suppressor Pathway (YAP/TAZ/TEAD/MST/LATS) and EGFR-RAS-RAF-MEK in cancer metastasis. Genes Dis, 8(1), 48–60. https://doi.org/10.1016/j.gendis.2019.11.003

    Article  CAS  PubMed  Google Scholar 

  • Zinatizadeh, M. R., Momeni, S. A., Zarandi, P. K., Chalbatani, G. M., Dana, H., Mirzaei, H. R., Miri, S. R., et al. (2019). The role and function of Ras-association domain family in cancer: a review. Genes & Diseases, 6(4), 378–384.

    CAS  Google Scholar 

  • Zipfel, P. A., Brady, D. C., Kashatus, D. F., Ancrile, B. D., Tyler, D. S., & Counter, C. M. (2010). Ral activation promotes melanomagenesis. Oncogene, 29(34), 4859–4864.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Mohammad Reza Zinatizadeh & Peyman Kheirandish Zarandi

  2. Cancer Biology Signaling Pathway Interest Group (CBSPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Mohammad Reza Zinatizadeh & Peyman Kheirandish Zarandi

  3. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mahsa Keshavarz-Fathi

  4. Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Mahsa Keshavarz-Fathi

  5. Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran

    Mohammad Hadi Yousefi

  6. Department of Mycobacteriology and Pulmonary Research, Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran

    Mohammad Hadi Yousefi

  7. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  8. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  9. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nima Rezaei

Authors
  1. Mohammad Reza Zinatizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peyman Kheirandish Zarandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahsa Keshavarz-Fathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Hadi Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nima Rezaei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Reza Zinatizadeh.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest in this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zinatizadeh, M.R., Zarandi, P.K., Keshavarz-Fathi, M. et al. The role of ral signaling and post translational modifications (PTMs) of Ras in cancer. GENOME INSTAB. DIS. 3, 22–32 (2022). https://doi.org/10.1007/s42764-022-00059-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42764-022-00059-0

Keywords

Search

Navigation