FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade.

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Citation

Kuchay S, Duan S, Schenkein E, Peschiaroli A, Saraf A, Florens L, Washburn MP, Pagano M

FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade.

Nat Cell Biol. 2013 May;15(5):472-80. doi: 10.1038/ncb2731. Epub 2013 Apr 21.

PubMed ID
23604317 [ View in PubMed
]
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 p85beta and tyrosine phosphatase PTPL1 as interacting proteins. FBXL2 interacts with the pool of p85beta that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation. FBXL2-mediated degradation of p85beta is dependent on the integrity of its CaaX motif. Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosphorylation of p85beta on Tyr 655, which is adjacent to the degron, inhibits p85beta binding to FBXL2. Dephosphorylation of phospho-Tyr-655 by PTPL1 stimulates p85beta binding to and degradation through FBXL2. Finally, defects in the FBXL2-mediated degradation of p85beta 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 p85beta levels, preventing the inhibition of PI(3)K by an excess of free p85 that could compete with p85-p110 heterodimers for IRS1.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Phosphatidylinositol 3-kinase regulatory subunit betaO00459Details