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A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2.

Sci Rep. 2016 Feb 03;6:20471
Susanne B Breitkopf 1 , Xuemei Yang 2 , Michael J Begley 3 , Meghana Kulkarni 4 , Yu-Hsin Chiu 5 , Alexa B Turke 6 , Jessica Lauriol 7 , Min Yuan 2 , Jie Qi 6 , Jeffrey A Engelman 6 , Pengyu Hong 8 , Maria I Kontaridis 9 , Lewis C Cantley 10 , Norbert Perrimon 4 , John M Asara 1
Susanne B Breitkopf 1 , Xuemei Yang 2 , Michael J Begley 3 , Meghana Kulkarni 4 , Yu-Hsin Chiu 5 , Alexa B Turke 6 , Jessica Lauriol 7 , Min Yuan 2 , Jie Qi 6 , Jeffrey A Engelman 6 , Pengyu Hong 8 , Maria I Kontaridis 9 , Lewis C Cantley 10 , Norbert Perrimon 4 , John M Asara 1
+ et al

[No authors listed]

Author information
  • 1 Harvard Medical School, Department of Medicine, Boston, MA USA.
  • 2 Beth Israel Deaconess Medical Center, Division of Signal Transduction, Boston, MA USA.
  • 3 Centers for Therapeutic Innovation, Pfizer, Boston, Massachusetts, USA.
  • 4 Howard Hughes Medical Institute, Harvard Medical School, Department of Genetics, Boston, MA USA.
  • 5 Novartis, Cambridge, MA USA.
  • 6 Massachusetts General Hospital, Center for Thoracic Cancers, Charlestown, MA USA.
  • 7 Beth Israel Deaconess Medical Center, Division of Cardiology, Boston, MA USA.
  • 8 Brandeis University, Department of Computer Science, Waltham, MA USA.
  • 9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA USA.
  • 10 Cancer Center, Weill Cornell Medical College, New York, NY USA.

摘要

Using a series of immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) experiments and reciprocal BLAST, we conducted a fly-human cross-species comparison of the phosphoinositide-3-kinase (PI3K) interactome in a drosophila S2R+ cell line and several NSCLC and human multiple myeloma cell lines to identify conserved interacting proteins to PI3K, a critical signaling regulator of the AKT pathway. Using H929 human cancer cells and drosophila S2R+ cells, our data revealed an unexpected direct binding of Corkscrew, the drosophila ortholog of the non-receptor protein tyrosine phosphatase type II (SHP2) to the Pi3k21B (p60) regulatory subunit of PI3K (p50/p85 human ortholog) but no association with Pi3k92e, the human ortholog of the p110 catalytic subunit. The p85-SHP2 association was validated in human cell lines, and formed a ternary regulatory complex with GRB2-associated-binding protein 2 (GAB2). Validation experiments with knockdown of GAB2 and Far-Western blots proved the direct interaction of SHP2 with p85, independent of adaptor proteins and transfected FLAG-p85 provided evidence that SHP2 binding on p85 occurred on the SH2 domains. A disruption of the SHP2-p85 complex took place after insulin/IGF1 stimulation or imatinib treatment, suggesting that the direct SHP2-p85 interaction was both independent of AKT activation and positively regulates the ERK signaling pathway.

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