Protein phosphatase 2A PR130/B″α1 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 (phosph...