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

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 controlvalve 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. Abbreviations used: cAMP – Cyclic adenosine monophosphate; RTK –Receptor Tyrosine Kinase; EGFR – Epidermal growth factor receptor; GEM – G protein exchange modulator; GEF – Guanine nucleotide exchange factor; GDI – Guanine nucleotide dissociation inhibitor; SH2 – Src homology 2; PM – plasma membrane; DAG – Diacylglycerol; EGF – Epidermal growth factor; AUC – Area under the curve; AC – Adenylyl cyclase; PDE – Phosphodiesterase; AMP – adenosine monophosptate; ATP – adenosine triphosphate; CDK5 – cyclin dependent kinase 5; PKC-✓ – Protein kinase C ✓; PLC– Phospholipase C ; Epac1 – Exchange factor directly activated by cAMP 1; RIA – Radioimmunoassay; IBMX – 3-isobutyl-1-methylxanthene. 2 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/149781 doi: bioRxiv preprint first posted online Jun. 13, 2017;