Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 9A, SE-40530 Gothenburg, Sweden.
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, USA.
Sci Signal. 2017 Oct 24;10(502):eaan0804. doi: 10.1126/scisignal.aan0804.
In , the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (Alk) and its ligand jelly belly (Jeb) are required to specify muscle founder cells in the visceral mesoderm. We identified a critical role for the scaffolding protein Cnk (connector enhancer of kinase suppressor of Ras) in this signaling pathway. Embryos that ectopically expressed the minimal Alk interaction region in the carboxyl terminus of Cnk or lacked maternal and zygotic did not generate visceral founder cells or a functional gut musculature, phenotypes that resemble those of and mutants. Deletion of the entire Alk-interacting region in the locus affected the Alk signaling pathway in the visceral mesoderm and not other RTK signaling pathways in other tissues. In addition, the Cnk-interacting protein Aveugle (Ave) was critical for Alk signaling in the developing visceral mesoderm. Alk signaling stimulates the MAPK/ERK pathway, but the scaffolding protein Ksr, which facilitates activation of this pathway, was not required to promote visceral founder cell specification. Thus, Cnk and Ave represent critical molecules downstream of Alk, and their loss genocopies the lack of visceral founder cell specification of and mutants, indicating their essential roles in Alk signaling.
在果蝇中，受体酪氨酸激酶（RTK）间变性淋巴瘤激酶（Alk）及其配体 jelly belly（Jeb）对于内脏中胚层中肌肉创始细胞的特化是必需的。我们确定支架蛋白 Cnk（激酶抑制剂 Ras 的连接增强子）在这个信号通路中起着关键作用。在 Cnk 羧基末端异位表达 Alk 最小相互作用区域的胚胎或缺乏母源和合子 时，不会产生内脏创始细胞或功能性肠道肌肉，其表型类似于 和 突变体。在 基因座中删除整个 Alk 相互作用区域会影响内脏中胚层中的 Alk 信号通路，而不会影响其他组织中的其他 RTK 信号通路。此外，发育中的内脏中胚层中 Alk 信号对于 Cnk 相互作用蛋白 Aveugle（Ave）是至关重要的。Alk 信号刺激 MAPK/ERK 通路，但促进该通路激活的支架蛋白 Ksr 对于促进内脏创始细胞特化并非必需。因此，Cnk 和 Ave 代表 Alk 下游的关键分子，它们的缺失模拟了 和 突变体缺乏内脏创始细胞特化的情况，表明它们在 Alk 信号中起着至关重要的作用。
