TY - JOUR T1 - Guanine-nucleotide Exchange Modulator, GIV/Girdin, Serves as a Tunable Valve for Growth Factor-Stimulated Cyclic AMP Signals JF - bioRxiv DO - 10.1101/149781 SP - 149781 AU - Michael Getz AU - Lee Swanson AU - Debashish Sahoo AU - Pradipta Ghosh AU - Padmini Rangamani Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/13/149781.abstract N2 - 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.cAMPCyclic adenosine monophosphateRTKReceptor Tyrosine KinaseEGFREpidermal growth factor receptorGEMG protein exchange modulatorGEFGuanine nucleotide exchange factorGDIGuanine nucleotide dissociation inhibitorSH2Src homology 2PMplasma membraneDAGDiacylglycerolEGFEpidermal growth factorAUCArea under the curveACAdenylyl cyclasePDEPhosphodiesteraseAMPadenosine monophosptateATPadenosine triphosphateCDK5cyclin dependent kinase 5PKC-θProtein kinase C θPLC-γPhospholipase C γEpac1Exchange factor directly activated by cAMP 1RIARadioimmunoassayIBMX3-isobutyl-1-methylxant heneAbbreviations:cAMPCyclic adenosine monophosphateRTKReceptor Tyrosine KinaseEGFREpidermal growth factor receptorGEMG protein exchange modulatorGEFGuanine nucleotide exchange factorGDIGuanine nucleotide dissociation inhibitorSH2Src homology 2PMplasma membraneDAGDiacylglycerolEGFEpidermal growth factorAUCArea under the curveACAdenylyl cyclasePDEPhosphodiesteraseAMPadenosine monophosptateATPadenosine triphosphateCDK5cyclin dependent kinase 5PKC-θProtein kinase C θPLC-γPhospholipase C γEpac1Exchange factor directly activated by cAMP 1RIARadioimmunoassayIBMX3-isobutyl-1-methylxant hene ER -