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Mitogen-Activated Protein Kinase Signaling and Cancer

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Protein Modifications in Pathogenic Dysregulation of Signaling

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Abstract

The mitogen-activated protein kinase (MAPK) signaling pathways consist of a three-tiered core of sequentially activated protein kinases, namely, MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK, and have essential roles in a wide range of biological processes such as proliferation, differentiation, and apoptosis. In mammals, three major families of MAPKs—ERK, JNK, and p38—have been characterized. Extracellular signal-regulated kinase (ERK) is mainly activated by mitogenic stimuli and is associated with proliferative responses, whereas JNK and p38 are preferentially activated by various environmental stresses and by cytokines, and are associated with inflammation, repair, and/or apoptotic responses. Rigorous control of MAPK signaling pathways is thus essential for elicitation of proper biological outcomes and for maintaining the homeostasis of the human body. Indeed, perturbation of these signaling systems is involved in a variety of life-threatening diseases, including cancer. In this chapter, we summarize recent advances in understanding the function and regulatory mechanisms of MAPK signaling systems, highlighting post-translational modifications including ubiquitin and ubiquitin-like modifiers. Roles of aberrant regulation of MAPK signaling in the etiology of human cancer are also discussed.

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References

  • Aebersold DM, Shaul YD, Yung Y, Yarom N, Yao Z, Hanoch T, Seger R (2004) Extracellular signal-regulated kinase 1c (ERK1c), a novel 42-kilodalton ERK, demonstrates unique modes of regulation, localization, and function. Mol Cell Biol 24:10000–10015

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Archambault V, Glover DM (2009) Polo-like kinases: conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol 10:265–275

    Article  PubMed  CAS  Google Scholar 

  • Arimoto K, Fukuda H, Imajoh-Ohmi S, Saito H, Takekawa M (2008) Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol 10:1324–1332

    Article  PubMed  CAS  Google Scholar 

  • Avruch J (2007) MAP kinase pathways: the first twenty years. Biochim Biophys Acta 1773:1150–1160

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bogani D, Siggers P, Brixey R, Warr N, Beddow S, Edwards J, Williams D, Wilhelm D, Koopman P, Flavell RA, Chi H, Ostrer H, Wells S, Cheeseman M, Greenfield A (2009) Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol 7:e1000196

    Article  PubMed  PubMed Central  Google Scholar 

  • Bromberg-White JL, Andersen NJ, Duesbery NS (2012) MEK genomics in development and disease. Brief Funct Genomics 11:300–310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cheng J, Bawa T, Lee P, Gong L, Yeh ET (2006) Role of desumoylation in the development of prostate cancer. Neoplasia 8:667–676

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chi H, Lu B, Takekawa M, Davis RJ, Flavell RA (2004) GADD45β/GADD45γ and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNγ production in T cells. EMBO J 23:1576–1586

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chi H, Sarkisian MR, Rakic P, Flavell RA (2005) Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci U S A 102:3846–3851

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Dentici ML, Sarkozy A, Pantaleoni F, Carta C, Lepri F, Ferese R, Cordeddu V, Martinelli S, Briuglia S, Digilio MC, Zampino G, Tartaglia M, Dallapiccola B (2009) Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. Eur J Hum Genet 17:733–740

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Deschenes-Simard X, Kottakis F, Meloche S, Ferbeyre G (2014) ERKs in cancer: friends or foes? Cancer Res 74:412–419

    Article  PubMed  CAS  Google Scholar 

  • Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B (2005) E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer. Nat Struct Mol Biol 12:933–934

    Article  PubMed  CAS  Google Scholar 

  • Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. Nature (Lond) 460:278–282

    Article  CAS  Google Scholar 

  • Gareau JR, Lima CD (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11:861–871

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gupta RK, Srinivas UK (2008) Heat shock induces chromosomal instability in near-tetraploid embryonal carcinoma cells. Cancer Biol Ther 7:1471–1480

    Article  PubMed  CAS  Google Scholar 

  • Hicke L, Schubert HL, Hill CP (2005) Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6:610–621

    Article  PubMed  CAS  Google Scholar 

  • Hickey CM, Wilson NR, Hochstrasser M (2012) Function and regulation of SUMO proteases. Nat Rev Mol Cell Biol 13:755–766

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Holderfield M, Deuker MM, McCormick F, McMahon M (2014) Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 14:455–467

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ Jr (1999) Genomic instability in Gadd45α-deficient mice. Nat Genet 23:176–184

    Article  PubMed  CAS  Google Scholar 

  • Ikushima H, Miyazono K (2010) TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 10:415–424

    Article  PubMed  CAS  Google Scholar 

  • Inanc B, Dodson H, Morrison CG (2010) A centrosome-autonomous signal that involves centriole disengagement permits centrosome duplication in G2 phase after DNA damage. Mol Biol Cell 21:3866–3877

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jang S, Atkins MB (2013) Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol 14:e60–e69

    Article  PubMed  CAS  Google Scholar 

  • Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Keil E, Hocker R, Schuster M, Essmann F, Ueffing N, Hoffman B, Liebermann DA, Pfeffer K, Schulze-Osthoff K, Schmitz I (2013) Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. Cell Death Differ 20:321–332

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kubota Y, O’Grady P, Saito H, Takekawa M (2011) Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation. Nat Cell Biol 13:282–291

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869

    PubMed  CAS  Google Scholar 

  • Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T (2002) The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol Cell 9:945–956

    Article  PubMed  CAS  Google Scholar 

  • Malakhov MP, Kim KI, Malakhova OA, Jacobs BS, Borden EC, Zhang DE (2003) High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transduction. J Biol Chem 278:16608–16613

    Article  PubMed  CAS  Google Scholar 

  • Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA (2004) Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature (Lond) 427:256–260

    Article  CAS  Google Scholar 

  • Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26:3227–3239

    Article  PubMed  CAS  Google Scholar 

  • Miyake Z, Takekawa M, Ge Q, Saito H (2007) Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol Cell Biol 27:2765–2776

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315:201–205

    Article  PubMed  CAS  Google Scholar 

  • Nakamura T, Saito H, Takekawa M (2013) SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nat Commun 4:1775

    Article  PubMed  Google Scholar 

  • Niehrs C, Schafer A (2012) Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol 22:220–227

    Article  PubMed  CAS  Google Scholar 

  • Peters S, Zimmermann S, Adjei AA (2014) Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions. Cancer Treat Rev 40:917–926

    Article  PubMed  CAS  Google Scholar 

  • Pickart CM, Eddins MJ (2004) Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta 1695:55–72

    Article  PubMed  CAS  Google Scholar 

  • Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26:3100–3112

    Article  PubMed  CAS  Google Scholar 

  • Rincon M, Davis RJ (2009) Regulation of the immune response by stress-activated protein kinases. Immunol Rev 228:212–224

    Article  PubMed  CAS  Google Scholar 

  • Rodrigues-Martins A, Riparbelli M, Callaini G, Glover DM, Bettencourt-Dias M (2007) Revisiting the role of the mother centriole in centriole biogenesis. Science 316:1046–1050

    Article  PubMed  CAS  Google Scholar 

  • Rosario CO, Ko MA, Haffani YZ, Gladdy RA, Paderova J, Pollett A, Squire JA, Dennis JW, Swallow CJ (2010) Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci U S A 107:6888–6893

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Salvador JM, Brown-Clay JD, Fornace AJ Jr (2013) Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv Exp Med Biol 793:1–19

    Article  PubMed  CAS  Google Scholar 

  • Sasaki AT, Carracedo A, Locasale JW, Anastasiou D, Takeuchi K, Kahoud ER, Haviv S, Asara JM, Pandolfi PP, Cantley LC (2011) Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci Signal 4:ra13

    Article  PubMed  PubMed Central  Google Scholar 

  • Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308

    Article  PubMed  CAS  Google Scholar 

  • Schwarte-Waldhoff I, Schmiegel W (2002) Smad4 transcriptional pathways and angiogenesis. Int J Gastrointest Cancer 31:47–59

    Article  PubMed  CAS  Google Scholar 

  • Stevens MV, Parker P, Vaillancourt RR, Camenisch TD (2006) MEKK4 regulates developmental EMT in the embryonic heart. Dev Dyn 235:2761–2770

    Article  PubMed  CAS  Google Scholar 

  • Takekawa M, Saito H (1998) A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95:521–530

    Article  PubMed  CAS  Google Scholar 

  • Takekawa M, Posas F, Saito H (1997) A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J 16:4973–4982

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Takekawa M, Tatebayashi K, Itoh F, Adachi M, Imai K, Saito H (2002) Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J 21:6473–6482

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (2012) GADD45 proteins: central players in tumorigenesis. Curr Mol Med 12:634–651

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9:537–549

    Article  PubMed  CAS  Google Scholar 

  • Winter-Vann AM, Johnson GL (2007) Integrated activation of MAP3Ks balances cell fate in response to stress. J Cell Biochem 102:848–858

    Article  PubMed  CAS  Google Scholar 

  • Yang SH, Jaffray E, Hay RT, Sharrocks AD (2003) Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity. Mol Cell 12:63–74

    Article  PubMed  CAS  Google Scholar 

  • Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q (2005) The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 11:6442–6449

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Cell Signaling & Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan

    Mutsuhiro Takekawa & Yuji Kubota

Authors
  1. Mutsuhiro Takekawa
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  2. Yuji Kubota
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Correspondence to Mutsuhiro Takekawa .

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Editors and Affiliations

  1. Division of Cellular & Molecular Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Jun-ichiro Inoue

  2. The Institute of Medical Science Division of Cell Signaling & Molecular Medicine, The University of Tokyo, Tokyo, Japan

    Mutsuhiro Takekawa

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Takekawa, M., Kubota, Y. (2015). Mitogen-Activated Protein Kinase Signaling and Cancer. In: Inoue, Ji., Takekawa, M. (eds) Protein Modifications in Pathogenic Dysregulation of Signaling. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55561-2_14

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