Rabex-5 ubiquitin ligase activity restricts Ras signaling to establish pathway homeostasis in Drosophila.
The Ras signaling pathway allows cells to translate external cues into diverse biological responses. Depending on context and the threshold reached, Ras signaling can promote growth, proliferation, differentiation, or cell survival. Failure to maintain precise control of Ras can have adverse physiological consequences. Indeed, excess Ras signaling disrupts developmental patterning and causes developmental disorders [1, 2], and in mature tissues, it can lead to cancer [3-5]. We identify Rabex-5 as a new component of Ras signaling crucial for achieving proper pathway outputs in multiple contexts in vivo. We show that Drosophila Rabex-5 restricts Ras signaling to establish organism size, wing vein pattern, and eye versus antennal fate. Rabex-5 has both Rab5 guanine nucleotide exchange factor (GEF) activity that regulates endocytic trafficking [6] and ubiquitin ligase activity [7, 8]. Surprisingly, overexpression studies demonstrate that Rabex-5 ubiquitin ligase activity, not its Rab5 GEF activity, is required to restrict wing vein specification and to suppress the eye phenotypes of oncogenic Ras expression. Furthermore, genetic interaction experiments indicate that Rabex-5 acts at the step of Ras, and tissue culture studies show that Rabex-5 promotes Ras ubiquitination. Together, these findings reveal a new mechanism for attenuating Ras signaling in vivo and suggest an important role for Rabex-5-mediated Ras ubiquitination in pathway homeostasis.
Yan
Hua
H
Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, NY 10029, USA.
Jahanshahi
Maryam
M
Horvath
Elizabeth A
EA
Liu
Hsiu-Yu
HY
Pfleger
Cathie M
CM
D000818:Animals; D049628:Body Size; D054910:Compound Eye, Arthropod / Q000254:growth & development / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis; D007814:Larva / Q000201:enzymology; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D018010:Receptors, Invertebrate Peptide / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014921:Wings, Animal / Q000254:growth & development; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D029721:Drosophila Proteins; D018010:Receptors, Invertebrate Peptide; D044767:Ubiquitin-Protein Ligases; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C553811:Rabex-5 protein, Drosophila