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Protein phosphatase 2A PR130/B''1 subunit binds to the SH2 domain-containing inositol polyphosphate 5-phosphatase 2 and prevents epidermal growth factor (EGF)-induced EGF receptor degradation sustaining EGF-mediated signaling

Karen Zwaenepoel^*, Jozef Goris^*, Christophe Erneux, Peter J. Parker^, and Veerle Janssens^*,1

^* Protein Phosphorylation and Proteomics Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium;

Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, Brussels, Belgium;

Protein Phosphorylation Laboratory, London Research Institute–Cancer Research UK, London, UK; and

Division of Cancer Studies, King’s College London, London, UK

¹ Correspondence: Protein Phosphorylation and Proteomics Laboratory, Dept. of Molecular Cell Biology, Faculty of Medicine, Gasthuisberg O&N1, Herestraat 49 Box 901, B-3000 Leuven, Belgium. E-mail: veerle.janssens{at}med.kuleuven.be

To elucidate novel cell biological functions of specific protein phosphatase 2A (PP2A) holoenzymes, we identified and biochemically characterized a complex between the Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2) and a PP2A holoenzyme comprising PR130/B''1 as a regulatory subunit (PP2A_T130) in several mammalian cell lines. PR130/B''1 and SHIP2 partially colocalize in untreated HeLa cells, and both translocate to the cell membrane on epidermal growth factor (EGF) stimulation. Concomitantly, a transient EGF-dependent interaction of PR130/B''1 with the EGF receptor (EGFR) was observed, whereas the SHIP2-PR130 interaction remained constitutive. As previously reported for SHIP2, RNA interference-mediated knockdown of PR130 in COS-7 cells resulted in increased EGF-induced proteasome-dependent EGFR degradation, and an increased interaction of EGFR with the E3 ligase c-Cbl. In concordance with faster EGFR clearance or desensitization, intrinsic EGFR kinase activity (phospho-Tyr-1068) and downstream protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways were more rapidly inactivated in PR130-knockdown cells. Notably, these effects could be rescued by reintroduction of RNA interference-resistant Myc-PR130, excluding any off-target effect. These data highlight a novel biological role of the PP2A_T130 holoenzyme in EGF signaling through interaction with EGFR and the phosphatidylinositol (3,4,5)-trisphosphate 5-phosphatase SHIP2. This interaction may be of clinical relevance as dysfunction of EGF-mediated signaling has been linked to various human cancers.—Zwaenepoel, K., Goris, J., Erneux, C., Parker, P.J., Janssens, V. Protein phosphatase 2A PR130/B''1 subunit binds to the SH2 domain-containing inositol polyphosphate 5-phosphatase 2 and prevents epidermal growth factor (EGF)-induced EGF receptor degradation sustaining EGF-mediated signaling.

Key Words: receptor tyrosine kinase • c-Cbl • Akt/protein kinase B • extracellular signal-regulated kinase