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.

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 Tyrosine Phosphatases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • 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
  • Phosphatidylinositol 3-Kinases
  • 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