Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi

Nicholas A Kalogriopoulos, Inmaculada Lopez-Sanchez, Changsheng Lin, Tony Ngo, Krishna K Midde, Suchismita Roy, Nicolas Aznar, Fiona Murray, Mikel Garcia-Marcos, Irina Kufareva, Majid Ghassemian, Pradipta Ghosh* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs cross-talk has been a long-standing question, but answers remain elusive. Using linear ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator dissociates Gαi•βγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the interdomain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell's decision to "go" vs. "grow." These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.

Original languageEnglish
Pages (from-to)28763-28774
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
Publication statusPublished - 17 Nov 2020

Keywords

  • heterotrimeric G proteins
  • growth factor receptor tyrosine kinases
  • EGFR
  • tyrosine
  • phosphorylation
  • transactivation

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