title: Platelet-derived growth factor (PDGF)-induced activation of Erk5 MAP-kinase is dependent on Mekk2, Mek1/2, PKC and PI3-kinase, and affects BMP signaling.
abstract: Platelet-derived growth factor-BB (PDGF-BB) binds to its tyrosine kinase receptors (PDGFRs) and stimulates mitogenicity and survival of cells of mesenchymal origin. Activation of PDGFRs initiates a number of downstream signaling pathways, including phosphatidyl 3'-inositol kinase (PI3-kinase), phospholipase Cγ and MAP kinase pathways. In this report, we show that Erk5 MAP kinase is activated in response to PDGF-BB in the smooth muscle cell line MOVAS in a manner dependent on Mekk2, Mek1/2, Mek5, PI3-kinase and protein kinase C (PKC). The co-operation of Mek1/2 and Mekk2 in the activation of Erk5, suggests a close co-regulation between the Erk1/2 and Erk5 MAP kinase pathways. Furthermore, we found that classical PKCs are important for Erk5 activation. In addition, we found that PKCζ interacts with Erk5 and may exert a negative feed-back effect. We observed no nuclear accumulation of Erk5 in response to PDGF-BB stimulation, however, we identified a mechanism by which cytoplasmic Erk5 influences gene expression; Erk5 was essential for PDGF-BB-mediated Smad1/5/8 signaling by stimulating release and/or activation of bone morphogenetic protein(s) (BMPs). Thus, PDGF-BB-induced Erk5 activation involves parallel stimulatory and inhibitory pathways and promotes Smad1/5/8 signaling.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsioumpekou
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
authors.forename: Natalia
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
authors.forename: Fatima
authors.initials: F
authors.lastname: Burovic
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden. Electronic address: Johan.Lennartsson@LICR.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051796:Inhibitor of Differentiation Proteins; D010982:Platelet-Derived Growth Factor; D051785:Smad Proteins; C067679:Idb3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048054:Mitogen-Activated Protein Kinase 7; D048730:MAP Kinase Kinase Kinase 2; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse
keywords: Erk5; MAP kinase; Mekk2; PDGFRβ; PKC; Smad