Work

Guanine-nucleotide Exchange Modulator, GIV/Girdin, Serves as a Tunable Valve for Growth Factor-Stimulated Cyclic AMP Signals

Year: 2017

Type: preprint

Abstract: Cellular levels of the versatile second messenger, cyclic-(c)AMP are regulated by the antagonistic actions of the canonical G protein→adenylyl cyclase pathway that is initiated by G-protein-coupled receptors (GPCRs) and by phosphodiesterases (PDEs); dysregulated cAMP signaling drives many diseases, including cancers. Recently, an alternative paradigm for cAMP signaling has emerged, in which growth factor-receptor tyrosine kinases (RTKs; e.g ., EGFR) access and modulate G proteins via cytosolic guanine-nucleotide exchange modulator (GEM), GIV/Girdin; dysregulation of this pathway is frequently encountered in cancers. Here we present a comprehensive network-based compartmental model for the paradigm of GEM-dependent signaling that reveals unforeseen crosstalk and network dynamics between upstream events and the various feedback-loops that fine-tune the GEM action of GIV, and captures the experimentally determined dynamics of cAMP. The model also reveals that GIV acts a tunable control-valve within the RTK→cAMP pathway; hence, it modulates cAMP via mechanisms distinct from the two most-often targeted classes of cAMP modulators, GPCRs and PDEs.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/149781

Authors: Michael Getz, Lee Swanson, Debashish Sahoo, Pradipta Ghosh, Padmini Rangamani

Institutions: Moores Cancer Center, University of California San Diego

Language: English

Topic: Phosphodiesterase function and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green