MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb.
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.
Kawakami
Yasuhiko
Y
The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA.
Rodríguez-León
Joaquín
J
Koth
Christopher M
CM
Büscher
Dirk
D
Itoh
Tohru
T
Raya
Angel
A
Ng
Jennifer K
JK
Esteban
Concepción Rodríguez
CR
Takahashi
Shigeru
S
Henrique
Domingos
D
Schwarz
May-Fun
MF
Asahara
Hiroshi
H
Izpisúa Belmonte
Juan Carlos
JC
D000818:Animals; D017209:Apoptosis; D002642:Chick Embryo; D054642:Dual Specificity Phosphatase 6; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D005121:Extremities / Q000196:embryology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D015027:Zebrafish
D054642:Dual Specificity Phosphatase 6; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C496457:Fgf8 protein, mouse; C517036:Dusp6 protein, mouse