Nature Cell Biology
5, 513 - 519 (2003)
Published online: 27 May 2003; | doi:10.1038/ncb989
MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limbYasuhiko Kawakami1, 6, Joaquín Rodríguez-León2, 6, Christopher M. Koth1, Dirk Büscher1, Tohru Itoh1, Ángel Raya1, Jennifer K. Ng1, Concepción Rodríguez Esteban1, Shigeru Takahashi3, Domingos Henrique2, 4, May-Fun Schwarz1, Hiroshi Asahara3, 5
& Juan Carlos Izpisúa Belmonte11
The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA. 2
Instituto Gulbenkian de Ciencia, Rua Da Quinta Grande n 6, Oeiras 2780-901, Portugal. 3
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. 4
Faculdade de Medicina de Lisboa, Instituto Histologia e Embriologia, Av Prof Egas Moniz, Lisboa 1649-028, Portugal. 5
PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan. 6
These authors contributed equally to this work.
Correspondence should be addressed to Juan Carlos Izpisúa Belmonte belmonte@salk.eduThe 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.
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