期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 9, 页码 E937-E946出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420140112
关键词
heterotrimeric G protein; growth factor receptor tyrosine kinase; Girdin; PI3-kinase; Akt; invasion; cyclic AMP
资金
- NIH [P30 NS047101, P30 CA23100, P01 DK054441]
- National Institutes of Health (NIH) [R01CA160911, R01 DK099226]
- Burroughs Wellcome Fund, Doris Duke Charitable Foundation (DDCF) Clinical Scientist Developmental Award [2010058]
- American Cancer Society [ACS-IRG 70-002]
- DDCF Grant [2013073]
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 G alpha-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-G alpha i ternary complexes are formed in living cells and that G alpha i 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 Gai 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.
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