Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells

Naoya Asai, Toshifumi Fukuda, Zaiqi Wu, Atsushi Enomoto, Vassilis Pachnis, Masahide Takahashi, Frank Costantini

研究成果: Article査読

75 被引用数 (Scopus)

抄録

The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/ mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/ AKT, and RAC1/JUN NH2-terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.

本文言語English
ページ(範囲)4507-4516
ページ数10
ジャーナルDevelopment
133
22
DOI
出版ステータスPublished - 11-2006
外部発表はい

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

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