Ras-independent activation of ERK signaling via the Torso receptor tyrosine kinase is mediated by Rap1

Snigdha Mishra, Sarah M. Smolik, Michael A. Forte, Philip J.S. Stork

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

In Drosophila embryos, the Torso receptor tyrosine kinase (RTK) activates the small G protein Ras (D-Ras1) and the protein kinase Raf (D-Raf) to activate ERK to direct differentiation of terminal structures [1]. However, genetic studies have demonstrated that Torso, and by extension other RTKs, can activate Raf and ERK independently of Ras [2]. In mammalian cells, the small G protein Rap1 has been proposed to couple RTKs to ERKs. However, the ability of Rap1 to activate ERKs remains controversial, in part because direct genetic evidence supporting this hypothesis is lacking. Here, we present biochemical and genetic evidence that D-Rap1, the Drosophila homolog of Rap1, can activate D-Raf and ERK. We show that D-Rap1 binds D-Raf and activates ERKs in a GTP- and D-Raf-dependent manner. Targeted disruption of D-Rap1 expression decreased both Torso-dependent ERK activation and the ERK-dependent expression of the zygotic genes tailless and huckebein to levels similar to those achieved in D-Ras1 null embryos. Furthermore, combined deficiencies of D-Ras1 and D-Rap1 completely abolished expression of these genes, mimicking the phenotype observed in embryos lacking D-Raf. These studies provide the first direct genetic evidence of Rap1-mediated activation of the MAP kinase cascade in eukaryotic organisms.

Original languageEnglish (US)
Pages (from-to)366-370
Number of pages5
JournalCurrent Biology
Volume15
Issue number4
DOIs
StatePublished - Feb 22 2005

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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