CXCL12 and C5a trigger cell migration via a PAK1/2-p38α MAPK-MAPKAP-K2-HSP27 pathway

Simon Rousseau (Lead / Corresponding author), Ignacio Dolado, Victoria Beardmore, Natalia Shpiro, Rudolfo Marquez, Angel R. Nebreda, J. Simon C. Arthur, Lauren M. Case, Marc Tessier-Lavigne, Matthias Gaestel, Ana Cuenda, Philip Cohen

    Research output: Contribution to journalArticlepeer-review

    100 Citations (Scopus)

    Abstract

    Cell migration is critical for many processes, such as angiogenesis, inflammation, development and wound healing, and is also involved in tumour progression and metastasis. Here we show that CXCL12, complement factor 5a (C5a), hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF)-BB, which stimulate cell migration, also activate p38α MAPK. Pharmacological inhibition of this protein kinase with SB 203580 or BIRB 0796, or the genetic ablation of p38α MAPK, blocked cell migration induced by the aforementioned chemo-attractants. Macrophages from mice lacking one or more of the other p38 MAPK isoforms showed normal cell migration in response to C5a. We also show that the activation of p38α MAPK in response to CXCL12 requires the p21-activated protein kinases (PAK)-1 and PAK-2. MAPKAP-K2 is a protein kinase that is activated by p38α MAPK. Reducing its expression using RNA interference blocked CXCL12-induced HeLa cell migration, while macrophages from mice that do not express MAPKAP-K2 failed to migrate in response to C5a. Moreover, RNA interference against the small heat shock protein 27 (HSP27), a physiological substrate of MAPKAP-K2, blocked the CXCL12-induced cell migration. These results demonstrate a general and essential role of the PAK-p38α MAPK-MAPKAP-K2-HSP27 signalling pathway in mediating the effects of chemotactic stimuli on cell migration.

    Original languageEnglish
    Pages (from-to)1897-1905
    Number of pages9
    JournalCellular Signalling
    Volume18
    Issue number11
    DOIs
    Publication statusPublished - 1 Nov 2006

    Keywords

    • Cell motility
    • HSP27
    • MAPKAP-K2
    • Metastasis
    • p38 MAPK
    • PAK

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