MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb

Yasuhiko Kawakami, Joaquín Rodríguez-León, Christopher M. Koth, Dirk Büscher, Tohru Itoh, Ángel Raya, Jennifer K. Ng, Concepción Rodríguez Esteban, Shigeru Takahashi, Domingos Henrique, May Fun Schwarz, Hiroshi Asahara, Juan Carlos Izpisúa Belmonte*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

232 Scopus citations


The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathways are involved in the regulatory mechanisms of several cellular processes including proliferation, differentiation and apoptosis. Here we show that during chick, mouse and zebrafish limb/fin development, a known MAPK/ERK regulator, Mkp3, is induced in the mesenchyme by fibroblast growth factor 8 (FGF8) signalling, through the PI(3)K/Akt pathway. This correlates with a high level of phosphorylated ERK in the apical ectodermal ridge (AER), where Mkp3 expression is excluded. Conversely, phosphorylated Akt is detected only in the mesenchyme. Constitutively active Mek1, as well as the downregulation of Mkp3 by small interfering RNA (siRNA), induced apoptosis in the mesenchyme. This suggests that MKP3 has a key role in mediating the proliferative, anti-apoptotic signalling of AER-derived FGF8.

Original languageEnglish (US)
Pages (from-to)513-519
Number of pages7
JournalNature Cell Biology
Issue number6
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Cell Biology

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