Abstract
Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates within tumors in vivo and protects tumor cells against cytotoxicity and apoptosis due to DNA damaging agents in vitro. Previous studies have established that SF-mediated cell protection involves antiapoptotic signaling from its receptor (c-Met) to PI3 kinase → c-Akt → Pak1 (p21-activated kinase -1) → NF-κB (nuclear factor-kappa B). Here, we found that Ras proteins (H-Ras and R-Ras) enhance SF-mediated activation of NF-κB and protection of DU-145 and MDCK (Madin–Darby canine kidney) cells against the topoisomerase IIα inhibitor adriamycin. Studies of Ras effector loop mutants and their downstream effectors suggest that Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF stimulation of NF-κB signaling and cell protection. Further studies revealed that Raf1 positively regulates the ability of SF to stimulate NF-κB activity and cell protection. The ability of Raf1 to stimulate NF-κB activity was not due to the classical Raf1 → MEK1/2 → ERK1/2 pathway. However, we found that a MEK3/6 → p38 pathway contributes to SF-mediated activation of NF-κB. In contrast, RalA, a target of the Ras/RalGDS pathway negatively regulated the ability of SF to stimulate NF-κB activity and cell protection. Ras, Raf1 and RalA modulate SF stimulation of NF-κB activity, in part, by regulating IκB kinase (IKK)-β kinase activity. These findings suggest that Ras/Raf1/RalA pathways may converge to modulate NF-κB activation and SF-mediated survival signaling at the IKK complex and/or a kinase upstream of this complex.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Albright CF, Giddings BW, Liu J, Vito M, Weinberg RA . (1993). Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J 12: 339–347.
Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL et al. (1988). Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48: 589–601.
Bardelli A, Longatti P, Albero D, Goruppi S, Schneider C, Ponzetto C et al. (1996). HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO J 15: 6205–6212.
Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR et al. (2000). Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc Natl Acad Sci USA 97: 4615–4620.
Bottaro DP, Rubin JS, Faletto DL, Chan AM-L, Kmiecik TE, Vande Woude GF et al. (1991). Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251: 802–804.
Bowers DC, Fan S, Walter K, Abounader R, Williams JA, Rosen EM et al. (2000). Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. Cancer Res 60: 4277–4283.
Camonis JH, White MA . (2005). Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol 15: 327–332. (Review).
Cantor SB, Urano T, Feig LA . (1995). Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Mol Cell Biol 15: 4578–4584.
Chung HH, Benson DR, Schultz PG . (1993). Probing the structure and mechanism of Ras protein with an expanded genetic code. Science 259: 806–809.
Cong LN, Chen H, Li Y, Zhou L, McGibbon MA, Taylor SI et al. (1997). Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol Endocrinol 11: 1881–1890.
Costantini C, Rossi F, Formaggio E, Bernardoni R, Cecconi D, Della-Bianca V . (2005). Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in beta-amyloid peptide-dependent cell death. J Mol Neurosci 25: 141–156.
de Vos AM, Tong L, Milburn MV, Matias PM, Jancarik J, Noguchi S et al. (1988). Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21. Science 239: 888–893.
Derijard B, Raingeaud J, Barrett T, Wu I-H, Han J, Ulevitch RJ et al. (1995). Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267: 682–685.
Fan S, Gao M, Meng Q, Laterra JJ, Symons MH, Coniglio S et al. (2005). Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. Oncogene 24: 1749–1766.
Fan S, Ma YX, Gao M, Yuan RQ, Meng Q, Goldberg ID et al. (2001). The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. Mol Cell Biol 21: 4968–4984.
Fan S, Ma YX, Wang J-A, Yuan R-Q, Meng Q, Laterra JJ et al. (2000). The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase. Oncogene 19: 2212–2223.
Fan S, Wang J-A, Yuan R-Q, Rockwell S, Andres J, Zlatapolskiy A et al. (1998). Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. Oncogene 17: 131–141.
Fitzgerald EM . (2000). Regulation of voltage-dependent calcium channels in rat sensory neurones involves a Ras-mitogen-activated protein kinase pathway. J Physiol 527: 433–444.
Frisch SM, Francis H . (1994). Disruption of epithelial cell–matrix interactions induces apoptosis. J Cell Biol 124: 619–626.
Graziani A, Gramaglia D, dalla Zonca P, Comoglio PM . (1993). Hepatocyte growth factor/scatter factor stimulates the Ras-guanine nucleotide exchanger. J Biol Chem 268: 9165–9168.
Herrmann C . (2003). Ras-effector interactions: after one decade. Curr Opin Struct Biol 13: 122–129. (Review).
Hofer F, Fields S, Schneider C, Martin GS . (1994). Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci USA 91: 11089–11093.
Hu MC, Wang Y . (1998). IkappaB kinase-alpha and -beta genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes. Gene 222: 31–40.
Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K et al. (1997). Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer 79: 749–760.
Kraus MH, Yuasa Y, Aaronson SA . (1984). A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc Natl Acad Sci USA 81: 5384–5388.
Lin A, Minden A, Martinetto H, Claret F-X, Lange-Carter C, Mercurio F et al. (1995). Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268: 286–290.
Luo JQ, Liu X, Frankel P, Rotunda T, Ramos M, Flom J et al. (1998). Functional association between Arf and RalA in active phospholipase D complex. Proc Natl Acad Sci USA 95: 3632–3637.
Matteucci E, Modora S, Simone M, Desiderio MA . (2003). Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency. Oncogene 22: 4062–4073.
May MJ, D'Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S . (2000). Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 289: 1550–1554.
McFarlin DR, Lindstrom MJ, Gould MN . (2003). Affinity with Raf is sufficient for Ras to efficiently induce rat mammary carcinomas. Carcinogenesis 24: 99–105.
Milburn MV, Tong L, deVos AM, Brunger A, Yamaizumi Z, Nishimura S et al. (1990). Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247: 939–945.
Mochizuki N, Ohba Y, Kobayashi S, Otsuka N, Graybiel AM, Tanaka S et al. (2000). Crk activation of JNK via C3G and R-Ras. J Biol Chem 275: 12667–12671.
Mody N, Campbell DG, Morrice N, Peggie M, Cohen P . (2003). An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Biochem J 372: 567–575.
Moodie SA, Willumsen BM, Weber MJ, Wolfman A . (1993). Complexes of Ras. GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260: 1658–1661.
Murai H, Ikeda M, Kishida S, Ishida O, Okazaki-Kishida M, Matsuura Y et al. (1997). Characterization of Ral GDP dissociation stimulator-like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral. J Biol Chem 272: 10483–10490.
Nick JA, Avdi NJ, Young SK, Lehman LA, McDonald PP, Frasch SC et al. (1999). Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. J Clin Invest 103: 851–858.
Oxford G, Owens CR, Titus BJ, Foreman TL, Herlevsen MC, Smith SC et al. (2005). RalA and RalB: antagonistic relatives in cancer cell migration. Cancer Res 65: 7111–7120.
Peyssonnaux C, Provot S, Felder-Schmittbuhl MP, Calothy G, Eychene A . (2000). Induction of postmitotic neuroretina cell proliferation by distinct Ras downstream signaling pathways. Mol Cell Biol 20: 7068–7079.
Rahman A, Anwar KN, Minhajuddin M, Bijli KM, Javaid K, True AL et al. (2004). cAMP targeting of p38 MAP kinase inhibits thrombin-induced NF-kappaB activation and ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol 287: L1017–L1024.
Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ . (1996). MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 16: 1247–1255.
Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P et al. (1997). Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89: 457–467.
Rosen EM, Lamszus K, Laterra J, Polverini PJ, Rubin JS, Goldberg ID . (1997). HGF/SF in angiogenesis. Ciba Found Symp 212: 215–226.
Shao H, Kadono-Okuda K, Finlin BS, Andres DA . (1999). Biochemical characterization of the Ras-related GTPases Rit and Rin. Arch Biochem Biophys 371: 207–219.
Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX et al. (2001). Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha/beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci USA 98: 8774–8779.
Song KS, Seong JK, Chung KC, Lee WJ, Kim CH, Cho KN et al. (2003). Induction of MUC8 gene expression by interleukin-1 beta is mediated by a sequential ERK MAPK/RSK1/CREB cascade pathway in human airway epithelial cells. J Biol Chem 278: 34890–34896.
Stewart S, Guan KL . (2000). The dominant-negative Ras mutant, N17Ras, can inhibit signaling independently of blocking Ras activation. J Biol Chem 275: 8854–8862.
Stuckler D, Singhal J, Singhal SS, Yadav S, Awasthi YC, Awasthi S . (2005). RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer Res 65: 991–998.
Tulasne D, Paumelle R, Weidner KM, Vandenbunder B, Fafeur V . (1999). The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering. Mol Biol Cell 10: 551–565.
Vitale N, Mawet J, Camonis J, Regazzi R, Bader MF, Chasserot-Golaz S . (2005). The small GTPase RalA controls exocytosis of large dense core secretory granules by interacting with ARF6-dependent phospholipase D1. J Biol Chem 280: 29921–29928.
Vojtek AB, Hollenberg SM, Cooper JA . (1993). Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74: 205–214.
Voss M, Weernink PA, Haupenthal S, Moller U, Cool RH, Bauer B et al. (1999). Phospholipase D stimulation by receptor tyrosine kinases mediated by protein kinase C and a Ras/Ral signaling cascade. J Biol Chem 274: 34691–34698.
Wang XS, Diener K, Manthey CL, Wang S, Rosenzweig B, Bray J et al. (1997). Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. J Biol Chem 272: 23668–23674.
Webb CP, Van Aelst L, Wigler MH, Woude GF . (1998). Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 95: 8773–8778.
White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M et al. (1995). Multiple Ras functions can contribute to mammalian cell transformation. Cell 80: 533–541.
Wohlgemuth S, Kiel C, Kramer A, Serrano L, Wittinghofer F, Herrmann C . (2005). Recognizing and defining true Ras binding domains I: biochemical analysis. J Mol Biol 348: 741–758.
Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV . (1997). IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 278: 866–869.
Yan M, Templeton DJ . (1994). Identification of 2 serine residues of MEK-1 that are differentially phosphorylated during activation by raf and MEK kinase. J Biol Chem 269: 19067–19073.
Yang JJ, Kang JS, Krauss RS . (1998). Ras signals to the cell cycle machinery via multiple pathways to induce anchorage-independent growth. Mol Cell Biol 18: 2586–2595.
Zheng CF, Guan KL . (1993). Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268: 23933–23939.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545.
Acknowledgements
Sources of support: This work is supported, in part, by United States Public Health Service Grants RO1-ES09169 (EMR) and RO1-NS43987 (JJL/EMR).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fan, S., Meng, Q., Laterra, J. et al. Ras effector pathways modulate scatter factor-stimulated NF-κB signaling and protection against DNA damage. Oncogene 26, 4774–4796 (2007). https://doi.org/10.1038/sj.onc.1210271
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210271
Keywords
This article is cited by
-
Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status
Scientific Reports (2020)
-
RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation
Nature Communications (2018)
-
Nuclear factor-κB signaling pathway is involved in phospholipase Cε-regulated proliferation in human renal cell carcinoma cells
Molecular and Cellular Biochemistry (2014)
-
Raf kinases in cancer–roles and therapeutic opportunities
Oncogene (2011)
-
Comparison of human chromosome 19q13 and syntenic region on mouse chromosome 7 reveals absence, in man, of 11.6 Mb containing four mouse calcium-sensing receptor-related sequences: relevance to familial benign hypocalciuric hypercalcaemia type 3
European Journal of Human Genetics (2010)