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

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

doi:10.1038/ncb989

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

Nat Cell Biol. 2003 Jun;5(6):513-9. doi: 10.1038/ncb989.

Authors

Yasuhiko Kawakami¹, Joaquín Rodríguez-León, Christopher M Koth, Dirk Büscher, Tohru Itoh, Angel Raya, Jennifer K Ng, Concepción Rodríguez Esteban, Shigeru Takahashi, Domingos Henrique, May-Fun Schwarz, Hiroshi Asahara, Juan Carlos Izpisúa Belmonte

Affiliation

¹ The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA.

PMID: 12766772
DOI: 10.1038/ncb989

Abstract

The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI3K)/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 PI3K/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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Apoptosis
Chick Embryo
Dual Specificity Phosphatase 6
Embryo, Nonmammalian / cytology
Embryo, Nonmammalian / metabolism
Enzyme Activation
Extremities / embryology*
Fibroblast Growth Factor 8
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / physiology*
Gene Expression Regulation, Developmental*
MAP Kinase Signaling System
Mice
Molecular Sequence Data
Morphogenesis
Phosphatidylinositol 3-Kinases / metabolism
Protein Serine-Threonine Kinases*
Protein Tyrosine Phosphatases / metabolism*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Signal Transduction*
Zebrafish

Substances

Fgf8 protein, mouse
Proto-Oncogene Proteins
Fibroblast Growth Factor 8
Fibroblast Growth Factors
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Dual Specificity Phosphatase 6
Dusp6 protein, mouse
Protein Tyrosine Phosphatases

Associated data

GENBANK/AY278202
GENBANK/AY278203
GENBANK/AY278204