Big Mitogen-Activated Protein Kinase 1 (BMK1)/Extracellular Signal Regulated Kinase 5 (ERK5) Is Involved in Platelet-Derived Growth Factor (PDGF)−Induced Vascular Smooth Muscle Cell Migration


Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal–regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1−SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5α, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1−SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.


  1. 1

    Lee JD, Ulevitch RJ, Han J : Primary structure of BMK1: a new mammalian map kinase. Biochem Biophys Res Commun 1995; 213: 715–724.

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Hayashi M, Lee JD : Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J Mol Med 2004; 82: 800–808.

    CAS  Article  Google Scholar 

  4. 4

    Suzaki Y, Yoshizumi M, Kagami S, et al: BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions. Kidney Int 2004; 65: 1749–1760.

    CAS  Article  Google Scholar 

  5. 5

    Ikeda Y, Aihara K, Sato T, et al: Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II–induced cardiac fibrosis. J Biol Chem 2005; 280: 29661–29666.

    CAS  Article  Google Scholar 

  6. 6

    Abe J, Kusuhara M, Ulevitch RJ, Berk BC, Lee JD : Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem 1996; 271: 16586–16590.

    CAS  Article  Google Scholar 

  7. 7

    Suzaki Y, Yoshizumi M, Kagami S, et al: Hydrogen peroxide stimulates c-Src–mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults. J Biol Chem 2002; 277: 9614–9621.

    CAS  Article  Google Scholar 

  8. 8

    Barros JC, Marshall CJ : Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J Cell Sci 2005; 118: 1663–1671.

    CAS  Article  Google Scholar 

  9. 9

    Hii CS, Anson DS, Costabile M, Mukaro V, Dunning K, Ferrante A : Characterization of the MEK5-ERK5 module in human neutrophils and its relationship to ERK1/ERK2 in the chemotactic response. J Biol Chem 2004; 279: 49825–49834.

    CAS  Article  Google Scholar 

  10. 10

    Karihaloo A, O'Rourke DA, Nickel C, Spokes K, Cantley LG : Differential MAPK pathways utilized for HGF- and EGF-dependent renal epithelial morphogenesis. J Biol Chem 2001; 276: 9166–9173.

    CAS  Article  Google Scholar 

  11. 11

    Pi X, Yan C, Berk BC : Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res 2004; 94: 362–369.

    CAS  Article  Google Scholar 

  12. 12

    Ross R : Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340: 115–126.

    CAS  Article  Google Scholar 

  13. 13

    Cunningham KS, Gotlieb AI : The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 2005; 85: 9–23.

    CAS  Article  Google Scholar 

  14. 14

    Touyz RM : Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol 2005; 90: 449–455.

    CAS  Article  Google Scholar 

  15. 15

    Mason DP, Kenagy RD, Hasenstab D, et al: Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res 1999; 85: 1179–1185.

    CAS  Article  Google Scholar 

  16. 16

    Kishi K, Muramatsu M, Jin D, et al: The effects of chymase on matrix metalloproteinase-2 activation in neointimal hyperplasia after balloon injury in dogs. Hypertens Res 2007; 30: 77–83.

    CAS  Article  Google Scholar 

  17. 17

    Yamamoto Y, Ogino K, Igawa G, et al: Allopurinol reduces neointimal hyperplasia in the carotid artery ligation model in spontaneously hypertensive rats. Hypertens Res 2006; 29: 915–921.

    Article  Google Scholar 

  18. 18

    Grotendorst GR, Seppa HE, Kleinman HK, Martin GR : Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci U S A 1981; 78: 3669–3672.

    CAS  Article  Google Scholar 

  19. 19

    Bilato C, Pauly RR, Melillo G, et al: Intracellular signaling pathways required for rat vascular smooth muscle cell migration. Interactions between basic fibroblast growth factor and platelet-derived growth factor. J Clin Invest 1995; 96: 1905–1915.

    CAS  Article  Google Scholar 

  20. 20

    Zhan Y, Kim S, Izumi Y, et al: Role of JNK, p38, and ERK in platelet-derived growth factor–induced vascular proliferation, migration, and gene expression. Arterioscler Thromb Vasc Biol 2003; 23: 795–801.

    CAS  Article  Google Scholar 

  21. 21

    Baxter RM, Secrist JP, Vaillancourt RR, Kazlauskas A : Full activation of the platelet-derived growth factor beta-receptor kinase involves multiple events. J Biol Chem 1998; 273: 17050–17055.

    CAS  Article  Google Scholar 

  22. 22

    Ronnstrand L, Arvidsson AK, Kallin A, et al: SHP-2 binds to Tyr763 and Tyr1009 in the PDGF beta-receptor and mediates PDGF-induced activation of the Ras/MAP kinase pathway and chemotaxis. Oncogene 1999; 18: 3696–3702.

    CAS  Article  Google Scholar 

  23. 23

    Saito Y, Hojo Y, Tanimoto T, Abe J, Berk BC : Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor. J Biol Chem 2002; 277: 23216–23222.

    CAS  Article  Google Scholar 

  24. 24

    Nakaoka Y, Nishida K, Fujio Y, et al: Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ Res 2003; 93: 221–229.

    CAS  Article  Google Scholar 

  25. 25

    Holgado-Madruga M, Wong AJ : Gab1 is an integrator of cell death versus cell survival signals in oxidative stress. Mol Cell Biol 2003; 23: 4471–4484.

    CAS  Article  Google Scholar 

  26. 26

    Yu CF, Liu ZX, Cantley LG : ERK negatively regulates the epidermal growth factor–mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem 2002; 277: 19382–19388.

    CAS  Article  Google Scholar 

  27. 27

    Isakoff SJ, Cardozo T, Andreev J, et al: Identification and analysis of PH domain–containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. EMBO J 1998; 17: 5374–5387.

    CAS  Article  Google Scholar 

  28. 28

    Izawa Y, Yoshizumi M, Fujita Y, et al: ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells. Exp Cell Res 2005; 308: 291–299.

    CAS  Article  Google Scholar 

  29. 29

    Kyaw M, Yoshizumi M, Tsuchiya K, et al: Antioxidants inhibit JNK and p38 MAPK activation but not ERK 1/2 activation by angiotensin II in rat aortic smooth muscle cells. Hypertens Res 2001; 24: 251–261.

    CAS  Article  Google Scholar 

  30. 30

    Kamakura S, Moriguchi T, Nishida E : Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 1999; 274: 26563–26571.

    CAS  Article  Google Scholar 

  31. 31

    Ishizawa K, Yoshizumi M, Tsuchiya K, et al: Dual effects of endothelin-1 (1–31): induction of mesangial cell migration and facilitation of monocyte recruitment through monocyte chemoattractant protein-1 production by mesangial cells. Hypertens Res 2004; 27: 433–440.

    CAS  Article  Google Scholar 

  32. 32

    Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, et al: Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance. J Biol Chem 2002; 277: 793–803.

    CAS  Article  Google Scholar 

  33. 33

    Moroi M, Zhang L, Yasuda T, et al: Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998; 101: 1225–1232.

    CAS  Article  Google Scholar 

  34. 34

    Tsukada S, Iwai M, Nishiu J, et al: Inhibition of experimental intimal thickening in mice lacking a novel G-protein–coupled receptor. Circulation 2003; 107: 313–319.

    CAS  Article  Google Scholar 

  35. 35

    Itoh M, Yoshida Y, Nishida K, Narimatsu M, Hibi M, Hirano T : Role of Gab1 in heart, placenta, and skin development and growth factor− and cytokine-induced extracellular signal–regulated kinase mitogen–activated protein kinase activation. Mol Cell Biol 2000; 20: 3695–3704.

    CAS  Article  Google Scholar 

  36. 36

    Zhou G, Bao ZQ, Dixon JE : Components of a new human protein kinase signal transduction pathway. J Biol Chem 1995; 270: 12665–12669.

    CAS  Article  Google Scholar 

  37. 37

    Zhao Q, Egashira K, Hiasa K, et al: Essential role of vascular endothelial growth factor and Flt-1 signals in neointimal formation after periadventitial injury. Arterioscler Thromb Vasc Biol 2004; 24: 2284–2289.

    CAS  Article  Google Scholar 

  38. 38

    Peppel K, Zhang L, Orman ES, et al: Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms. Cardiovasc Res 2005; 65: 674–682.

    CAS  Article  Google Scholar 

  39. 39

    Kingsley K, Huff JL, Rust WL, et al: ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5. Biochem Biophys Res Commun 2002; 293: 1000–1006.

    CAS  Article  Google Scholar 

  40. 40

    Graf K, Xi XP, Yang D, Fleck E, Hsueh WA, Law RE : Mitogen-activated protein kinase activation is involved in platelet-derived growth factor–directed migration by vascular smooth muscle cells. Hypertension 1997; 29: 334–339.

    CAS  Article  Google Scholar 

  41. 41

    Cameron SJ, Abe J, Malik S, Che W, Yang J : Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation. J Biol Chem 2004; 279: 1506–1512.

    CAS  Article  Google Scholar 

  42. 42

    Ishizawa K, Izawa Y, Ito H, et al: Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension 2005; 46: 1046–1052.

    CAS  Article  Google Scholar 

  43. 43

    Chang Y, Zhuang D, Zhang C, Hassid A : Increase of PTP levels in vascular injury and in cultured aortic smooth muscle cells treated with specific growth factors. Am J Physiol Heart Circ Physiol 2004; 287: H2201–H2208.

    CAS  Article  Google Scholar 

  44. 44

    Kallin A, Demoulin JB, Nishida K, Hirano T, Ronnstrand L, Heldin CH : Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor. J Biol Chem 2004; 279: 17897–17904.

    CAS  Article  Google Scholar 

  45. 45

    Akaike M, Che W, Marmarosh NL, et al: The hinge-helix 1 region of peroxisome proliferator–activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal–regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells. Mol Cell Biol 2004; 24: 8691–8704.

    CAS  Article  Google Scholar 

  46. 46

    Wang Y : Fill a Gab(1) in cardiac hypertrophy signaling: search a missing link between gp130 and ERK5 in hypertrophic remodeling in heart. Circ Res 2003; 93: 186–188.

    CAS  Article  Google Scholar 

  47. 47

    Cameron SJ, Itoh S, Baines CP, et al: Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. FEBS Lett 2004; 566: 255–260.

    CAS  Article  Google Scholar 

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Correspondence to Toshiaki Tamaki.

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Izawa, Y., Yoshizumi, M., Ishizawa, K. et al. Big Mitogen-Activated Protein Kinase 1 (BMK1)/Extracellular Signal Regulated Kinase 5 (ERK5) Is Involved in Platelet-Derived Growth Factor (PDGF)−Induced Vascular Smooth Muscle Cell Migration. Hypertens Res 30, 1107–1117 (2007).

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  • big mitogen-activated protein kinase 1/extracellular signal regulated kinase 5
  • platelet-derived growth factor
  • vascular smooth muscle cells
  • Src homology 2−containing protein tyrosine phophatase-2
  • vascular remodeling

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