FBXL2- and PTPL1-mediated degradation of p110-free p85? regulatory subunit controls the PI(3)K signalling cascade.

ABSTRACT: F-box proteins are the substrate-recognition subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Purification of the F-box protein FBXL2 identified the PI(3)K regulatory subunit p85? and tyrosine phosphatase PTPL1 as interacting proteins. FBXL2 interacts with the pool of p85? that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation. FBXL2-mediated degradation of p85? is dependent on the integrity of its CaaX motif. Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosphorylation of p85? on Tyr 655, which is adjacent to the degron, inhibits p85? binding to FBXL2. Dephosphorylation of phospho-Tyr-655 by PTPL1 stimulates p85? binding to and degradation through FBXL2. Finally, defects in the FBXL2-mediated degradation of p85? inhibit the binding of p110 subunits to IRS1, attenuate the PI(3)K signalling cascade and promote autophagy. We propose that FBXL2 and PTPL1 suppress p85? levels, preventing the inhibition of PI(3)K by an excess of free p85 that could compete with p85-p110 heterodimers for IRS1.

SUBMITTER: Kuchay S 

PROVIDER: S-EPMC3865866 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature