Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

MKK signaling and vascularization

Abstract

In 1998, George Vande Woude's lab discovered that anthrax lethal factor (LF), the principal virulence component of anthrax toxin, was a zinc-metalloprotease that cleaved and inactivated mitogen-activated protein kinase kinases (MKK). It was perhaps not surprising, given the known roles of MKK1 and 2 in cell proliferation, that LF was subsequently found to dramatically inhibit tumor growth in vivo. What was not anticipated, however, was that the tumors treated with LF would have a substantially reduced vascular content. This intriguing result was one of the first indications that MKK signaling plays an important role in promoting tumor vascularization in vivo. In the following short review, we will compare in vitro and in vivo evidence that supports the hypothesis that MKK signaling pathways are essential for vascularization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Accession codes

Accessions

Ensembl

GenBank/EMBL/DDBJ

References

  • Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S et al. (2000). Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 6: 109–116.

    Article  CAS  Google Scholar 

  • Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y et al. (2005). Germline mutations in HRAS protooncogene cause Costello syndrome. Nat Genet 37: 1038–1040.

    Article  CAS  Google Scholar 

  • Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL et al. (2004). Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 10: 849–857.

    Article  CAS  Google Scholar 

  • Beardmore VA, Hinton HJ, Eftychi C, Apostolaki M, Armaka M, Darragh J et al. (2005). Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol 25: 10454–10464.

    Article  CAS  Google Scholar 

  • Belanger LF, Roy S, Tremblay M, Brott B, Steff AM, Mourad W et al. (2003). Mek2 is dispensable for mouse growth and development. Mol Cell Biol 23: 4778–4787.

    Article  CAS  Google Scholar 

  • Bonnesen B, Orskov C, Rasmussen S, Holst PJ, Christensen JP, Eriksen KW et al. (2005). MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver. Blood 106: 3396–3404.

    Article  CAS  Google Scholar 

  • Bradley KA, Mogridge J, Mourez M, Collier RJ, Young JA . (2001). Identification of the cellular receptor for anthrax toxin. Nature 414: 225–229.

    Article  CAS  Google Scholar 

  • Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M et al. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435–439.

    Article  CAS  Google Scholar 

  • Chang L, Karin M . (2001). Mammalian MAP kinase signalling cascades. Nature 410: 37–40.

    Article  CAS  Google Scholar 

  • Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B et al. (2001). MAP kinases. Chem Rev 101: 2449–2476.

    Article  CAS  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 USA 102: 3846–3851.

    Article  CAS  Google Scholar 

  • Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ et al. (1989). Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84: 1470–1478.

    Article  CAS  Google Scholar 

  • D'Angelo G, Struman I, Martial J, Weiner RI . (1995). Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc Natl Acad Sci USA 92: 6374–6378.

    Article  CAS  Google Scholar 

  • Davis RJ . (2000). Signal transduction by the JNK group of MAP kinases. Cell 103: 239–252.

    Article  CAS  Google Scholar 

  • Dong C, Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA . (1998). Defective T cell differentiation in the absence of Jnk1. Science 282: 2092–2095.

    Article  CAS  Google Scholar 

  • Duesbery NS, Resau J, Webb CP, Koochekpour S, Koo HM, Leppla SH et al. (2001). Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways. Proc Natl Acad Sci USA 98: 4089–4094.

    Article  CAS  Google Scholar 

  • Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD et al. (1998). Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280: 734–737.

    Article  CAS  Google Scholar 

  • Eliceiri BP, Klemke R, Stromblad S, Cheresh DA . (1998). Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol 140: 1255–1263.

    Article  CAS  Google Scholar 

  • Ennis BW, Fultz KE, Smith KA, Westwick JK, Zhu D, Boluro-Ajayi M et al. (2005). Inhibition of tumor growth, angiogenesis, and tumor cell proliferation by a small molecule inhibitor of c-Jun N-terminal kinase. J Pharm Exp Therap 313: 325–332.

    Article  CAS  Google Scholar 

  • Ergun S, Kilic N, Wurmbach JH, Ebrahimnejad A, Fernando M, Sevinc S et al. (2001). Endostatin inhibits angiogenesis by stabilization of newly formed endothelial tubes. Angiogenesis 4: 193–206.

    Article  CAS  Google Scholar 

  • Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA . (2006). HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A 140: 8–16.

    Article  Google Scholar 

  • Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS et al. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439–442.

    Article  CAS  Google Scholar 

  • Ferrara N, Henzel WJ . (1989). Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161: 851–858.

    Article  CAS  Google Scholar 

  • Fong GH, Rossant J, Gertsenstein M, Breitman ML . (1995). Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376: 66–70.

    Article  CAS  Google Scholar 

  • Fong GH, Zhang L, Bryce DM, Peng J . (1999). Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126: 3015–3025.

    CAS  PubMed  Google Scholar 

  • Fragale A, Tartaglia M, Wu J, Gelb BD . (2004). Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 23: 267–277.

    Article  CAS  Google Scholar 

  • Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow MA et al. (1998). SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc Natl Acad Sci USA 95: 6881–6886.

    Article  CAS  Google Scholar 

  • Giroux S, Tremblay M, Bernard D, Cardin-Girard JF, Aubry S, Larouche L et al. (1999). Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol 9: 369–372.

    Article  CAS  Google Scholar 

  • Gripp KW . (2005). Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137: 72–77.

    Article  Google Scholar 

  • Hatano N, Mori Y, Oh-hora M, Kosugi A, Fujikawa T, Nakai N et al. (2003). Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells 8: 847–856.

    Article  CAS  Google Scholar 

  • Hayashi M, Fearns C, Eliceiri B, Yang Y, Lee JD . (2005). Big mitogen-activated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis. Cancer Res 65: 7699–7706.

    Article  CAS  Google Scholar 

  • Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B et al. (2004). Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest 113: 1138–1148.

    Article  CAS  Google Scholar 

  • Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D et al. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284: 1994–1998.

    Article  CAS  Google Scholar 

  • Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R et al. (2002). Tumor regression by targeted gene delivery to the neovasculature. Science 296: 2404–2407.

    Article  CAS  Google Scholar 

  • Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA . (2003). Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 162: 933–943.

    Article  CAS  Google Scholar 

  • Huser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S et al. (2001). MEK kinase activity is not necessary for Raf-1 function. EMBO J 20: 1940–1951.

    Article  CAS  Google Scholar 

  • Johnson GL, Lapadat R . (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298: 1911–1912.

    Article  CAS  Google Scholar 

  • Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B et al. (2004). PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet 41: e117.

    Article  CAS  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS et al. (1993). Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841–844.

    Article  CAS  Google Scholar 

  • Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG . (2005). PTPN11 (SHP2) mutations in leopard syndrome have dominant negative, not activating, effects. J Biol Chem 281: 6785–6792.

    Article  Google Scholar 

  • Kowanetz M, Ferrara N . (2006). Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 12: 5018–5022.

    Article  CAS  Google Scholar 

  • Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ et al. (1999). Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 18: 1845–1857.

    Article  CAS  Google Scholar 

  • Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al. (2001). Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7: 1194–1201.

    Article  CAS  Google Scholar 

  • MacKeigan JP, Collins TS, Ting JP . (2000). MEK inhibition enhances paclitaxel-induced tumor apoptosis. J Biol Chem 275: 38953–38956.

    Article  CAS  Google Scholar 

  • Matsumoto T, Turesson I, Book M, Gerwins P, Claesson-Welsh L . (2002). p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis. J Cell Biol 156: 149–160.

    Article  CAS  Google Scholar 

  • Merks JH, Caron HN, Hennekam RC . (2005). High incidence of malformation syndromes in a series of 1073 children with cancer. Am J Med Genet A 134: 132–143.

    Article  Google Scholar 

  • Mikula M, Schreiber M, Husak Z, Kucerova L, Ruth J, Wieser R et al. (2001). Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J 20: 1952–1962.

    Article  CAS  Google Scholar 

  • Milanini J, Vinals F, Pouyssegur J, Pages G . (1998). p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem 273: 18165–18172.

    Article  CAS  Google Scholar 

  • Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S et al. (2000). Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci USA 97: 10454–10459.

    Article  CAS  Google Scholar 

  • Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A et al. (2006). Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38: 294–296.

    Article  CAS  Google Scholar 

  • Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, De la Pompa JL et al. (1999). Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 126: 505–516.

    CAS  PubMed  Google Scholar 

  • Pages G, Berra E, Milanini J, Levy AP, Pouyssegur J . (2000). Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J Biol Chem 275: 26484–26491.

    Article  CAS  Google Scholar 

  • Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F et al. (1999). Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286: 1374–1377.

    Article  CAS  Google Scholar 

  • Pedram A, Razandi M, Levin ER . (1998). Extracellular signal-regulated protein kinase/Jun kinase cross-talk underlies vascular endothelial cell growth factor-induced endothelial cell proliferation. J Biol Chem 273: 26722–26728.

    Article  CAS  Google Scholar 

  • Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K . (2002). Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci USA 99: 9248–9253.

    Article  CAS  Google Scholar 

  • Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV et al. (1986). New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement – the CFC syndrome. Am J Med Genet 25: 413–427.

    Article  CAS  Google Scholar 

  • Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Santa Cruz M et al. (2006). Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311: 1287–1290.

    Article  CAS  Google Scholar 

  • Rousseau S, Houle F, Landry J, Huot J . (1997). p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15: 2169–2177.

    Article  CAS  Google Scholar 

  • Roux PP, Blenis J . (2004). ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68: 320–344.

    Article  CAS  Google Scholar 

  • Ruegg C, Mariotti A . (2003). Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci 60: 1135–1157.

    Article  CAS  Google Scholar 

  • Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N et al. (2003). An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4: 964–968.

    Article  CAS  Google Scholar 

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF . (1983). Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985.

    Article  CAS  Google Scholar 

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML et al. (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62–66.

    Article  CAS  Google Scholar 

  • Shin EY, Kim SY, Kim EG . (2001). c-Jun N-terminal kinase is involved in motility of endothelial cell. Expt Mol Med 33: 276–283.

    Article  CAS  Google Scholar 

  • Sohn SJ, Sarvis BK, Cado D, Winoto A . (2002). ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J Biol Chem 277: 43344–43351.

    Article  CAS  Google Scholar 

  • St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E et al. (2000). Genes expressed in human tumor endothelium. Science 289: 1197–1202.

    Article  CAS  Google Scholar 

  • Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M . (2000). Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102: 221–231.

    Article  CAS  Google Scholar 

  • Tanaka N, Kamanaka M, Enslen H, Dong C, Wysk M, Davis RJ et al. (2002). Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO Rep 3: 785–791.

    Article  CAS  Google Scholar 

  • Tartaglia M, Gelb BD . (2005). Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet 6: 45–68.

    Article  CAS  Google Scholar 

  • Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C . (2000). Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J 352 (Part 3): 739–745.

    Article  CAS  Google Scholar 

  • Wang X, Merritt AJ, Seyfried J, Guo C, Papadakis ES, Finegan KG et al. (2005). Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol Cell Biol 25: 336–345.

    Article  Google Scholar 

  • Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H et al. (2004). BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099–7109.

    Article  CAS  Google Scholar 

  • Wojnowski L, Zimmer AM, Beck TW, Hahn H, Bernal R, Rapp UR et al. (1997). Endothelial apoptosis in Braf-deficient mice. Nat Genet 16: 293–297.

    Article  CAS  Google Scholar 

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . (1995). Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326–1331.

    Article  CAS  Google Scholar 

  • Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JS . (2003). Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol 3: 11.

    Article  Google Scholar 

  • Yang D, Tournier C, Wysk M, Lu HT, Xu J, Davis RJ et al. (1997). Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. Proc Natl Acad Sci USA 94: 3004–3009.

    Article  CAS  Google Scholar 

  • Yang DD, Conze D, Whitmarsh AJ, Barrett T, Davis RJ, Rincon M et al. (1998). Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity 9: 575–585.

    Article  CAS  Google Scholar 

  • Yang J, Boerm M, McCarty M, Bucana C, Fidler IJ, Zhuang Y et al. (2000). Mekk3 is essential for early embryonic cardiovascular development. Nat Genet 24: 309–313.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank J MacKeigan and J Young for their critical comments on the manuscript. PD and YD are supported by NIH grants CA108438 and CA109308, respectively.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N S Duesbery.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Depeille, P., Ding, Y., Bromberg-White, J. et al. MKK signaling and vascularization. Oncogene 26, 1290–1296 (2007). https://doi.org/10.1038/sj.onc.1210198

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210198

Keywords

This article is cited by

Search

Quick links