細胞の「ショートサーキット」を追う(Chasing Down a Cellular ‘Short Circuit’)

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2024-06-04 カリフォルニア大学サンディエゴ校(UCSD)

細胞の「ショートサーキット」を追う(Chasing Down a Cellular ‘Short Circuit’)Growth factors trigger G proteins (in green) to disengage from GPCRs and change localization within cells. At right: A ribbon diagram of the G protein structure shows the position of all phosphoevents the “buzzer” site in red. Photo credit: UC San Diego Health Sciences

カリフォルニア大学サンディエゴ校の研究者たちは、細胞内経路の「短絡」の原因を特定し、多くの人間の疾患の発生メカニズムに新たな光を当てました。この研究は「Science Signaling」に発表され、成長因子とGタンパク質共役受容体(GPCR)の間のクロストークを解明しました。GPCRは多くの疾患に関連するシグナル伝達経路に関与しており、FDA承認薬の約34%がこれを標的にしています。成長因子がGタンパク質をGPCRから奪い、シグナル伝達を妨げることが明らかになりました。この発見は、癌などの新しい治療法の開発に影響を与える可能性があります。

<関連情報>

成長因子に依存したGαiのリン酸化がGタンパク質共役型受容体による正常シグナル伝達を形成する Growth factor–dependent phosphorylation of Gαi shapes canonical signaling by G protein–coupled receptors

SUCHISMITA ROY, SAPTARSHI SINHA, ANANTA JAMES SILAS, MAJID GHASSEMIAN, […], AND PRADIPTA GHOSH
Science Signaling  Published:4 Jun 2024
DOI:https://doi.org/10.1126/scisignal.ade8041

Editor’s summary

In addition to being activated by GPCRs, heterotrimeric G proteins can be transactivated by receptor tyrosine kinases, including epidermal growth factor receptor (EGFR). Roy et al. investigated mechanisms of cross-talk between the GPCR CXCR4 and EGFR. Mass spectrometry analysis identified Gαi residues that were phosphorylated in response to EGF. Studies of Gαi proteins mutated at these sites showed that Gαi phosphorylation prevented it from subsequently coupling to CXCR4, in one case because of the cytosolic mislocalization of Gαi. Together, these findings suggest that cross-talk between growth factor receptors and GPCRs may be mediated at the level of Gαi phosphorylation. —John F. Foley

Abstract

A long-standing question in the field of signal transduction is how distinct signaling pathways interact with each other to control cell behavior. Growth factor receptors and G protein–coupled receptors (GPCRs) are the two major signaling hubs in eukaryotes. Given that the mechanisms by which they signal independently have been extensively characterized, we investigated how they may cross-talk with each other. Using linear ion trap mass spectrometry and cell-based biophysical, biochemical, and phenotypic assays, we found at least three distinct ways in which epidermal growth factor affected canonical G protein signaling by the Gi-coupled GPCR CXCR4 through the phosphorylation of Gαi. Phosphomimicking mutations in two residues in the αE helix of Gαi (tyrosine-154/tyrosine-155) suppressed agonist-induced Gαi activation while promoting constitutive Gβγ signaling. Phosphomimicking mutations in the P loop (serine-44, serine-47, and threonine-48) suppressed Gi activation entirely, thus completely segregating growth factor and GPCR pathways. As expected, most of the phosphorylation events appeared to affect intrinsic properties of Gαi proteins, including conformational stability, nucleotide binding, and the ability to associate with and to release Gβγ. However, one phosphomimicking mutation, targeting the carboxyl-terminal residue tyrosine-320, promoted mislocalization of Gαi from the plasma membrane, a previously uncharacterized mechanism of suppressing GPCR signaling through G protein subcellular compartmentalization. Together, these findings elucidate not only how growth factor and chemokine signals cross-talk through the phosphorylation-dependent modulation of Gαi but also how such cross-talk may generate signal diversity.

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