Research ArticleDevelopmental Biology

The scaffolding protein Cnk binds to the receptor tyrosine kinase Alk to promote visceral founder cell specification in Drosophila

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Sci. Signal.  24 Oct 2017:
Vol. 10, Issue 502, eaan0804
DOI: 10.1126/scisignal.aan0804

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Identifying downstream components of Alk

Aberrant activation of the receptor tyrosine kinase ALK contributes to the progression of several human cancers. In developing Drosophila larvae, Alk and its ligand Jeb are critical for the specification of visceral muscle founder cells. Wolfstetter et al. found that the scaffolding protein Cnk interacted with Alk and was required for Alk signaling in the visceral mesoderm of this model organism. In addition, the Cnk binding partner Ave promoted the function of Cnk in this pathway. Mutants deficient in Cnk or Ave or overexpressing the Alk binding region of Cnk (which would be expected to disrupt the interaction between Alk and Cnk) lacked founder cells and failed to develop functional gut musculature. Together, these results identify components downstream of Alk. Future studies are necessary to determine whether human homologs of Cnk also participate in ALK signaling.

Abstract

In Drosophila melanogaster, 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 cnk did not generate visceral founder cells or a functional gut musculature, phenotypes that resemble those of jeb and Alk mutants. Deletion of the entire Alk-interacting region in the cnk 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 Alk and jeb mutants, indicating their essential roles in Alk signaling.

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