PgmNr D1110: The subcellular distribution of Tribbles is linked to the regulation of growth and patterning by insulin and BMP signaling pathways.

Authors:
L. L. Dobens; Zachary Fischer; Jin-Yuan Fan; Alexander Nail


Institutes
Univ Missouri, Kansas City, Kansas City, MO.


Keyword: insulin signaling

Abstract:

The pseudokinase Tribbles is a conserved adaptor protein that binds and mediates the proteasomal degradation of key signaling mediators to balance tissue growth and proliferation. Tribbles family members are found in all animals and share conserved targets, notably Akt kinase, which Tribbles binds and degrades to block insulin responses.  Recently, mammalian Tribbles 3, has been shown to bind SMURF to block Smad 4 degradation and promote BMP signaling in tissue culture cells. We used a structure-function analysis of the highly conserved central pocket domain of Tribbles to identify a mutation Trbl[SLE/G] that changes the protein’s subcellular distribution from cortical/nuclear to strongly cortical. This change in subcellular distribution of Trbl[SLE/G] results in a strong block of Akt phosphorylation and insulin-mediated growth. Misexpression of Trbl[SLE/G] in the wing unexpectedly disrupts cross vein formation suggesting that Tribbles may regulate BMP signaling and in support of this, we observe increased levels of phosphoMad levels in cell misexpressing Trbl[SLE/G]. We will present on-going work in several model tissues to test the notion that the conserved pocket domain of Tribbles regulates its subcellular distribution with consequent effects on BMP- and insulin-mediated growth.



Flybase Genetic Index:
1. FlyBase gene symbol: trbl
2. FlyBase gene symbol: Mad