GqPCR-stimulated dephosphorylation of AKT is induced by an IGBP1-mediated PP2A switch

Guy Nadel, Zhong Yao, Ehud Wainstein, Izel Cohen, Ido Ben-Ami, Amir Schajnovitz, Galia Maik-Rachline, Zvi Naor, Benjamin A. Horwitz, Rony Seger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH. Methods: Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein–protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage. Results: We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation. Conclusion: Our results show a stimulated shift of PP2Ac from PI3K to AKT termed “PP2A switch” that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation. [MediaObject not available: see fulltext.].

Original languageEnglish
Article number5
JournalCell Communication and Signaling
Issue number1
StatePublished - Dec 2022


FundersFunder number
Samuil and Petr Polsky Prostate Cancer Research Fund
Israel Science Foundation


    • AKT
    • IGBP1
    • PI3K
    • PKC
    • PP2A


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