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.
- 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-θ
- Protein kinase C θ
- PLC-γ
- Phospholipase C γ
- Epac1
- Exchange factor directly activated by cAMP 1
- RIA
- Radioimmunoassay
- IBMX
- 3-isobutyl-1-methylxant hene
- 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-θ
- Protein kinase C θ
- PLC-γ
- Phospholipase C γ
- Epac1
- Exchange factor directly activated by cAMP 1
- RIA
- Radioimmunoassay
- IBMX
- 3-isobutyl-1-methylxant hene