Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):E937-46. doi: 10.1073/pnas.1420140112. Epub 2015 Feb 17.

Multimodular biosensors reveal a novel platform for activation of G proteins by growth factor receptors.

Author information

1
Departments of Medicine and.
2
Pharmacology and.
3
Departments of Medicine and Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 prghosh@ucsd.edu.

Abstract

Environmental cues are transmitted to the interior of the cell via a complex network of signaling hubs. Receptor tyrosine kinases (RTKs) and trimeric G proteins are two such major signaling hubs in eukaryotes. Conventionally, canonical signal transduction via trimeric G proteins is thought to be triggered exclusively by G protein-coupled receptors. Here we used molecular engineering to develop modular fluorescent biosensors that exploit the remarkable specificity of bimolecular recognition, i.e., of both G proteins and RTKs, and reveal the workings of a novel platform for activation of G proteins by RTKs in single living cells. Comprised of the unique modular makeup of guanidine exchange factor Gα-interacting vesicle-associated protein (GIV)/girdin, a guanidine exchange factor that links G proteins to a variety of RTKs, these biosensors provide direct evidence that RTK-GIV-Gαi ternary complexes are formed in living cells and that Gαi is transactivated within minutes after growth factor stimulation at the plasma membrane. Thus, GIV-derived biosensors provide a versatile strategy for visualizing, monitoring, and manipulating the dynamic association of Gαi with RTKs for noncanonical transactivation of G proteins in cells and illuminate a fundamental signaling event regulated by GIV during diverse cellular processes and pathophysiologic states.

KEYWORDS:

Akt; Girdin; PI3-kinase; cyclic AMP; growth factor receptor tyrosine kinase; heterotrimeric G protein; invasion

PMID:
25713130
PMCID:
PMC4352799
DOI:
10.1073/pnas.1420140112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center