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
2016 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 28, no 9, 1422-1431 p.Article in journal (Refereed) Published
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 C gamma 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 cooperation 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 PKC zeta 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. (C) 2016 Published by Elsevier Inc.
Place, publisher, year, edition, pages
2016. Vol. 28, no 9, 1422-1431 p.
Erk5, PDGFR beta, Mekk2, MAP kinase, PKC, Smad
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-302674DOI: 10.1016/j.cellsig.2016.06.013ISI: 000380595500027PubMedID: 27339033OAI: oai:DiVA.org:uu-302674DiVA: diva2:967459
FunderSwedish Cancer Society, 140332