title: FBXL2- and PTPL1-mediated degradation of p110-free p85β 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 p85β and tyrosine phosphatase PTPL1 as interacting proteins. FBXL2 interacts with the pool of p85β that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation. FBXL2-mediated degradation of p85β is dependent on the integrity of its CaaX motif. Whereas most SCF substrates require phosphorylation to interact with their F-box proteins, phosphorylation of p85β on Tyr 655, which is adjacent to the degron, inhibits p85β binding to FBXL2. Dephosphorylation of phospho-Tyr-655 by PTPL1 stimulates p85β binding to and degradation through FBXL2. Finally, defects in the FBXL2-mediated degradation of p85β 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 p85β levels, preventing the inhibition of PI(3)K by an excess of free p85 that could compete with p85-p110 heterodimers for IRS1.
authors.affiliation: Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.
authors.forename: Shafi
authors.initials: S
authors.lastname: Kuchay
authors.forename: Shanshan
authors.initials: S
authors.lastname: Duan
authors.forename: Emily
authors.initials: E
authors.lastname: Schenkein
authors.forename: Angelo
authors.initials: A
authors.lastname: Peschiaroli
authors.forename: Anita
authors.initials: A
authors.lastname: Saraf
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
mesh_terms: D001343:Autophagy; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C122028:FBXL2 protein, human; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D034741:RNA, Small Interfering; D014443:Tyrosine; D058543:Class Ia Phosphatidylinositol 3-Kinase; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D046988:Proteasome Endopeptidase Complex