The metastasis suppressor Nm23 as a modulator of Ras/ERK signaling

Journal of Molecular Signaling

Krisztina Takács-Vellai¹ 

[1] Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter stny. 1/C, H-1117 Budapest, Hungary

关键词: Scaffold;    Kinase suppressor of Ras (KSR);    Ras/ERK signaling;    Kinase;    Nucleoside-diphosphate kinase (NDPK);    Nm23;    Metastasis inhibitor;   

Others  :  802227
DOI  :  10.1186/1750-2187-9-4

 received in 2013-12-10, accepted in 2014-04-30,  发布年份 2014

【 摘 要 】

NM23-H1 (also known as NME1) was the first identified metastasis suppressor, which displays a nucleoside diphosphate kinase (NDPK) and histidine protein kinase activity. NDPKs are linked to many processes, such as cell migration, proliferation, differentiation, but the exact mechanism whereby NM23-H1 inhibits the metastatic potential of cancer cells remains elusive. However, some recent data suggest that NM23-H1 may exert its anti-metastatic effect by blocking Ras/ERK signaling. In mammalian cell lines NDPK-mediated attenuation of Ras/ERK signaling occurs through phosphorylation (thus inactivation) of KSR (kinase suppressor of Ras) scaffolds. In this review I summarize our knowledge about KSR’s function and its regulation in mammals and in C. elegans. Genetic studies in the nematode contributed substantially to our understanding of the function and regulation of the Ras pathway (i.e. KSR’s discovery is also linked to the nematode). Components of the RTK/Ras/ERK pathway seem to be highly conserved between mammals and worms. NDK-1, the worm homolog of NM23-H1 affects Ras/MAPK signaling at the level of KSRs, and a functional interaction between NDK-1/NDPK and KSRs was first demonstrated in the worm in vivo. However, NDK-1 is a factor, which is necessary for proper MAPK activation, thus it activates rather than suppresses Ras/MAPK signaling in the worm. The contradiction between results in mammalian cell lines and in the worm regarding NDPKs’ effect exerted on the outcome of Ras signaling might be resolved, if we better understand the function, structure and regulation of KSR scaffolds.

【 授权许可】

   
2014 Takács-Vellai; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME: Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 1988, 80:200-204.
• [2]Marino N, Marshall J-C, Steeg PS: Protein-protein interactions: a mechanism regulating the anti-metastatic properties of Nm23-H1. Naunyn Schmiedebergs Arch Pharmacol 2011, 384:351-362.
• [3]Boissan M, Wendum D, Arnaud-Dabernat S, Munier A, Debray M, Lascu I, Daniel J-Y, Lacombe M-L: Increased lung metastasis in transgenic NM23-Null/SV40 mice with hepatocellular carcinoma. J Natl Cancer Inst 2005, 97:836-845.
• [4]Desvignes T, Pontarotti P, Fauvel C, Bobe J: Nme protein family evolutionary history, a vertebrate perspective. BMC Evol Biol 2009, 9:256. BioMed Central Full Text
• [5]Boissan M, Dabernat S, Peuchant E, Schlattner U, Lascu I, Lacombe M-L: The mammalian Nm23/NDPK family: from metastasis control to cilia movement. Mol Cell Biochem 2009, 329:51-62.
• [6]Hsu T: NME genes in epithelial morphogenesis. Naunyn Schmiedebergs Arch Pharmacol 2011, 384:363-372.
• [7]Marino N, Nakayama J, Collins JW, Steeg PS: Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene. Cancer Metastasis Rev 2012, 31:593-603.
• [8]Boissan M, De Wever O, Lizarraga F, Wendum D, Poincloux R, Chignard N, Desbois-Mouthon C, Dufour S, Nawrocki-Raby B, Birembaut P, Bracke M, Chavrier P, Gespach C, Lacombe M-L: Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells. Cancer Res 2010, 70:7710-7722.
• [9]Palacios F, Schweitzer JK, Boshans RL, D’Souza-Schorey C: ARF6-GTP recruits Nm23-H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat Cell Biol 2002, 4:929-936.
• [10]Otsuki Y, Tanaka M, Yoshii S, Kawazoe N, Nakaya K, Sugimura H: Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci U S A 2001, 98:4385-4390.
• [11]Krishnan KS, Rikhy R, Rao S, Shivalkar M, Mosko M, Narayanan R, Etter P, Estes PS, Ramaswami M: Nucleoside diphosphate kinase, a source of GTP, is required for dynamin-dependent synaptic vesicle recycling. Neuron 2001, 30:197-210.
• [12]Dammai V, Adryan B, Lavenburg KR, Hsu T: Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development. Genes Dev 2003, 17:2812-2824.
• [13]Nallamothu G, Woolworth JA, Dammai V, Hsu T: Awd, the homolog of metastasis suppressor gene Nm23, regulates Drosophila epithelial cell invasion. Mol Cell Biol 2008, 28:1964-1973.
• [14]Hartsough MT, Morrison DK, Salerno M, Palmieri D, Ouatas T, Mair M, Patrick J, Steeg PS: Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem 2002, 277:32389-32399.
• [15]Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS: Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Mol Cell Biol 2005, 25:1379-1388.
• [16]Lee M-Y, Jeong W-J, Oh J-W, Choi K-Y: NM23H2 inhibits EGF- and Ras-induced proliferation of NIH3T3 cells by blocking the ERK pathway. Cancer Lett 2009, 275:221-226.
• [17]Tso PH, Wang Y, Yung LY, Tong Y, Lee MMK, Wong YH: RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras. Cell Signal 2013, 25:1064-1074.
• [18]Masoudi N, Fancsalszky L, Pourkarimi E, Vellai T, Alexa A, Reményi A, Gartner A, Mehta A, Takács-Vellai K: The NM23-H1/H2 homolog NDK-1 is required for full activation of Ras signaling in C. elegans. Development 2013, 140:3486-3495.
• [19]McKay MM, Morrison DK: Integrating signals from RTKs to ERK/MAPK. Oncogene 2007, 26:3113-3121.
• [20]Tidyman WE, Rauen KA: The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 2009, 19:230-236.
• [21]Karnoub AE, Weinberg RA: Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 2008, 9:517-531.
• [22]Udell CM, Rajakulendran T, Sicheri F, Therrien M: Mechanistic principles of RAF kinase signaling. Cell Mol Life Sci 2011, 68:553-565.
• [23]Shaul YD, Seger R: The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 2007, 1773:1213-1226.
• [24]Sundaram MV: Canonical RTK-Ras-ERK signaling and related alternative pathways. WormBook 2013. The Online Review of C. elegans Biology (ed. The C. elegans Research Community), doi/10.1895/wormbook.1.80.2, http://www.wormbook.org webcite
• [25]Sternberg PW: Vulval development. WormBook 2005. The Online Review of C. elegans Biology (ed. The C. elegans Research Community), doi:10.1895/wormbook.1.6.1, http://www.wormbook.org webcite.
• [26]Kornfeld K, Hom DB, Horvitz HR: The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 1995, 83:903-913.
• [27]Sundaram M, Han M: The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 1995, 83:889-901.
• [28]Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM: KSR, a novel protein kinase required for RAS signal transduction. Cell 1995, 83:879-888.
• [29]Ohmachi M, Rocheleau CE, Church D, Lambie E, Schedl T, Sundaram MV: C. elegans ksr-1 and ksr-2 have both unique and redundant functions and are required for MPK-1 ERK phosphorylation. Curr Biol 2002, 12:427-433.
• [30]Church DL, Guan KL, Lambie EJ: Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. Development 1995, 121:2525-2535.
• [31]Lee M-H, Ohmachi M, Arur S, Nayak S, Francis R, Church D, Lambie E, Schedl T: Multiple functions and dynamic activation of MPK-1 extracellular signal-regulated kinase signaling in Caenorhabditis elegans germline development. Genetics 2007, 177:2039-2062.
• [32]Klutho PJ, Costanzo-Garvey DL, Lewis RE: Regulation of glucose homeostasis by KSR1 and MARK2. PLoS One 2011, 6:e29304.
• [33]Lozano J, Xing R, Cai Z, Jensen HL, Trempus C, Mark W, Cannon R, Kolesnick R: Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res 2003, 63:4232-4238.
• [34]Nguyen A, Burack WR, Stock JL, Kortum R, Chaika OV, Afkarian M, Muller WJ, Murphy KM, Morrison DK, Lewis RE, McNeish J, Shaw AS: Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol Cell Biol 2002, 22:3035-3045.
• [35]Kortum RL, Costanzo DL, Haferbier J, Schreiner SJ, Razidlo GL, Wu M-H, Volle DJ, Mori T, Sakaue H, Chaika NV, Chaika OV, Lewis RE: The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Mol Cell Biol 2005, 25:7592-7604.
• [36]Revelli J-P, Smith D, Allen J, Jeter-Jones S, Shadoan MK, Desai U, Schneider M, van Sligtenhorst I, Kirkpatrick L, Platt KA, Suwanichkul A, Savelieva K, Gerhardt B, Mitchell J, Syrewicz J, Zambrowicz B, Hamman BD, Vogel P, Powell DR: Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. Obesity (Silver Spring) 2011, 19:1010-1018.
• [37]Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, Fernandez MR, Fisher K, Kortum RL, Hong E-G, Jun JY, Ko HJ, Schreiner A, Volle DJ, Treece T, Swift AL, Winer M, Chen D, Wu M, Leon LR, Shaw AS, McNeish J, Kim JK, Morrison DK, Tschöp MH, Lewis RE: KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab 2009, 10:366-378.
• [38]Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli J-P, Hendricks A, Keogh JM, Henning E, Doree D, Jeter-Jones S, Garg S, Bochukova EG, Bounds R, Ashford S, Gayton E, Hindmarsh PC, Shield JPH, Crowne E, Barford D, Wareham NJ, O’Rahilly S, Murphy MP, Powell DR, Barroso I, Farooqi IS: KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell 2013, 155:765-777.
• [39]Morrison DK: KSR: a MAPK scaffold of the Ras pathway? J Cell Sci 2001, 114(Pt 9):1609-1612.
• [40]Roy F, Laberge G, Douziech M, Ferland-McCollough D, Therrien M: KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev 2002, 16:427-438.
• [41]Alexa A, Varga J, Reményi A: Scaffolds are “active” regulators of signaling modules. FEBS J 2010, 277:4376-4382.
• [42]Müller J, Ory S, Copeland T, Piwnica-Worms H, Morrison DK: C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell 2001, 8:983-993.
• [43]Roy F, Therrien M: MAP kinase module: the Ksr connection. Curr Biol 2002, 12:R325-R327.
• [44]Michaud NR, Therrien M, Cacace A, Edsall LC, Spiegel S, Rubin GM, Morrison DK: KSR stimulates Raf-1 activity in a kinase-independent manner. Proc Natl Acad Sci U S A 1997, 94:12792-12796.
• [45]Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K: Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev 1999, 13:163-175.
• [46]Yu W, Fantl WJ, Harrowe G, Williams LT: Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr Biol 1998, 8:56-64.
• [47]Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJS, Kornev AP, Taylor SS, Shaw AS: Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 2013, 154:1036-1046.
• [48]Brennan DF, Dar AC, Hertz NT, Chao WCH, Burlingame AL, Shokat KM, Barford D: A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature 2011, 472:366-369.
• [49]McKay MM, Ritt DA, Morrison DK: RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling. Curr Biol 2011, 21:563-568.
• [50]Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA: Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 2004, 427:256-260.
• [51]Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK: Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 2003, 13:1356-1364.
• [52]Yoder JH, Chong H, Guan K-L, Han M: Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase. EMBO J 2004, 23:111-119.
• [53]Rocheleau CE, Rönnlund A, Tuck S, Sundaram MV: Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling. Proc Natl Acad Sci U S A 2005, 102:11757-11762.
• [54]Steeg PS, Palmieri D, Ouatas T, Salerno M: Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer. Cancer Lett 2003, 190:1-12.
• [55]Kao G, Tuck S, Baillie D, Sundaram MV: C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites. Development 2004, 131:755-765.
• [56]Eisenmann DM, Kim SK: Protruding vulva mutants identify novel loci and Wnt signaling factors that function during Caenorhabditis elegans vulva development. Genetics 2000, 156:1097-1116.
• [57]Cui M, Han M: Cis regulatory requirements for vulval cell-specific expression of the Caenorhabditis elegans fibroblast growth factor gene egl-17. Dev Biol 2003, 257:104-116.
• [58]Dard N, Peter M: Scaffold proteins in MAP kinase signaling: more than simple passive activating platforms. Bioessays 2006, 28:146-156.
• [59]Bell B, Xing H, Yan K, Gautam N, Muslin AJ: KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. J Biol Chem 1999, 274:7982-7986.
• [60]Hippe H-J, Wolf NM, Abu-Taha I, Mehringer R, Just S, Lutz S, Niroomand F, Postel EH, Katus HA, Rottbauer W, Wieland T: The interaction of nucleoside diphosphate kinase B with Gbetagamma dimers controls heterotrimeric G protein function. Proc Natl Acad Sci U S A 2009, 106:16269-16274.
• [61]Nunn C, Mao H, Chidiac P, Albert PR: RGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling. Semin Cell Dev Biol 2006, 17:390-399.
• [62]Dong MQ, Chase D, Patikoglou GA, Koelle MR: Multiple RGS proteins alter neural G protein signaling to allow C. elegans to rapidly change behavior when fed. Genes Dev 2000, 14:2003-2014.
• [63]Porter MY, Koelle MR: Insights into RGS Protein Function from Studies in Caenorhabditis Elegans. Prog Mol Biol Transl Sci 2009, 86:15-47. doi:10.1016/S1877-1173(09)86002-X