Rac1-stimulated macropinocytosis enhances Gβγ activation of PI3Kβ

Zahra Erami, Bassem D. Khalil, Gilbert Salloum, Yanhua Yao, Jaclyn LoPiccolo, Aliaksei Shymanets, Bernd Nürnberg, Anne R. Bresnick, Jonathan M. Backer

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Phosphoinositide 3-kinases (PI 3-kinases) are regulated by a diverse range of upstream activators, including receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and small GTPases from the Ras, Rho and Rab families. For the Class IA PI 3-kinase PI3Kβ, two mechanisms for GPCR-mediated regulation have been described: direct binding of Gβ? subunits to the C2-helical domain linker of p110β, and Dock180/ Elmo1-mediated activation of Rac1, which binds to the Ras-Binding Domain of p110β. We now show that the integration of these dual pathways is unexpectedly complex. In breast cancer cells, expression of constitutively activated Rac1 (CA-Rac1) along with either GPCR stimulation or expression of Gβ? led to an additive PI3Kβ-dependent activation of Akt. Whereas CA-Rac1-mediated activation of Akt was blocked in cells expressing a mutated PI3Kβ that cannot bind Gβ?, Gβ? and GPCR-mediated activation of Akt was preserved when Rac1 binding to PI3Kβ was blocked. Surprisingly, PI3Kβ-dependent CARac1 signaling to Akt was still seen in cells expressing a mutant p110β that cannot bind Rac1. Instead of directly binding to PI3Kβ, CA-Rac1 acts by enhancing Gβ? coupling to PI3Kβ, as CA-Rac1-mediated Akt activation was blocked by inhibitors of Gβ?. Cells expressing CA-Rac1 exhibited a robust induction of macropinocytosis, and inhibitors of macropinocytosis blocked the activation of Akt by CA-Rac1 or lysophosphatidic acid. Our data suggest that Rac1 can potentiate the activation of PI3Kβ by GPCRs through an indirect mechanism, by driving the formation of macropinosomes that serve as signaling platforms for Gβ? coupling to PI3Kβ.

Original languageEnglish (US)
Pages (from-to)3903-3914
Number of pages12
JournalBiochemical Journal
Volume474
Issue number23
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Erami, Z., Khalil, B. D., Salloum, G., Yao, Y., LoPiccolo, J., Shymanets, A., Nürnberg, B., Bresnick, A. R., & Backer, J. M. (2017). Rac1-stimulated macropinocytosis enhances Gβγ activation of PI3Kβ. Biochemical Journal, 474(23), 3903-3914. https://doi.org/10.1042/BCJ20170279