title: The Kinase Activity-deficient Isoform of the Protein Araf Antagonizes Ras/Mitogen-activated Protein Kinase (Ras/MAPK) Signaling in the Zebrafish Embryo.
abstract: Raf kinases are important components of the Ras-Raf-Mek-Erk pathway and also cross-talk with other signaling pathways. Araf kinase has been demonstrated to inhibit TGF-β/Smad2 signaling by directly phosphorylating and accelerating degradation of activated Smad2. In this study, we show that the araf gene expresses in zebrafish embryos to produce a shorter transcript variant, araf-tv2, in addition to the full-length variant araf-tv1. araf-tv2 is predicted to encode a C-terminally truncated peptide without the kinase activity domain. Araf-tv2 can physically associate with Araf-tv1 but does not antagonize the inhibitory effect of Araf-tv1 on TGF-β/Smad2 signaling. Instead, Araf-tv2 interacts strongly with Kras and Nras, ultimately blocking MAPK activation by these Ras proteins. In zebrafish embryos, overexpression of araf-tv2 is sufficient to inhibit Fgf/Ras-promoted Erk activation, mesodermal induction, dorsal development, and neuroectodermal posteriorization. Therefore, different isoforms of Araf may participate in similar developmental processes but by regulating different signaling pathways.
authors: From the State-Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 10084, China.
authors: Cong
authors: C
authors: Xiong
authors: From the State-Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 10084, China.
authors: Xingfeng
authors: X
authors: Liu
authors: From the State-Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 10084, China mengam@mail.tsinghua.edu.cn.
authors: Anming
authors: A
authors: Meng
mesh_terms: D000818:Animals; D002460:Cell Line; D047108:Embryonic Development; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology*
chemical_list: D007527:Isoenzymes; D005346:Fibroblast Growth Factors; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases
keywords: Araf; Ras protein; embryo; fibroblast growth factor (FGF); mesoderm; mitogen-activated protein kinase (MAPK); patterning; transcript variant; zebrafish