MKP3 negatively modulates PDGF-induced Akt and Erk5 phosphorylation as well as chemotaxis
2012 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 3, 635-640 p.Article in journal (Refereed) Published
MAP kinase phosphatase-3 (MKP3), also known as DUSP6 or Pyst1, is a dual specificity phosphatase considered to selectively dephosphorylate extracellular-signal-regulated kinase 1/2 (Erk1/2). Here, we report that in NIH3T3 cells, MKP3 is induced in response to platelet-derived growth factor (PDGF)-BB treatment in an Erk1/2- and phosphatidylinositol 3-kinase (PI3K)-dependent manner, but independently of Erk5 expression. Silencing of MKP3 expression did not affect PDGF-BB-induced Erk1/2 or p38 phosphorylation; however, their basal level of phosphorylation was elevated. Furthermore, we found that PDGF-BB-mediated activation of Erk5 and Akt was enhanced when the MKP3 expression was reduced. Interfering with Mek1/2 or PI3K using the inhibitors CI-1040 and LY-294002, respectively, inhibited PDGF-BB-induced MKP3 expression. Functionally, we found that MKP3 silencing did not affect cell proliferation, but enhanced the chemotactic response toward PDGF-BB. Although both Akt and Erk5 have been linked to increased cell survival, downregulation of MKP3 did not alter the ability of PDGF-BB to protect NIH3T3 cells from starvation-induced apoptosis. However, we observed an increased apoptosis in untreated cells with reduced MKP3 expression. In summary, our data indicate that there is negative cross-talk between Erk1/2 and Erk5 that involves regulation of MKP3 expression, and that PI3K in addition to promoting Akt phosphorylation also negatively modulates Akt, through MKP3 expression.
Place, publisher, year, edition, pages
2012. Vol. 24, no 3, 635-640 p.
Non-Smads, Smads, TAK1, TGF beta, TRAF6
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-168808DOI: 10.1016/j.cellsig.2011.11.001ISI: 000300478400007PubMedID: 22100392OAI: oai:DiVA.org:uu-168808DiVA: diva2:503464