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Protein phosphatase 2A PR130/B”α: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

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″α1 as a regulatory subunit (PP2AT130)in several mammalian cell lines. PR130/B″α1 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″α1 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 PP2AT130 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″α1 subunit binds to the SH2 domaincontaining inositol polyphosphate 5‐phosphatase 2 and prevents epidermal growth factor (EGF)‐induced EGF receptor degradation sustaining EGF‐mediated signaling. FASEB J. 24, 538–547 (2010). www.fasebj.org