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Mol Biol Cell. 2019 Jun 15;30(13):1621-1633. doi: 10.1091/mbc.E18-10-0630. Epub 2019 Apr 24.

A predictive computational model reveals that GIV/girdin serves as a tunable valve for EGFR-stimulated cyclic AMP signals.

Author information

1
Chemical Engineering Graduate Program, University of California, San Diego, La Jolla, CA 92093.
2
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
3
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
4
Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093.
5
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
6
Moores Comprehensive Cancer Center, University of California, San Diego, La Jolla, CA 92093.
7
Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093.

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 attenuated by phosphodiesterases (PDEs). Dysregulated cAMP signaling drives many diseases; for example, its low levels facilitate numerous sinister properties of cancer cells. 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 a cytosolic guanine-nucleotide exchange modulator (GEM), GIV/girdin; dysregulation of this pathway is frequently encountered in cancers. In this study, we present a network-based compartmental model for the paradigm of GEM-facilitated cross-talk between RTKs and G proteins and how that impacts cellular cAMP. Our model predicts that cross-talk between GIV, Gαs, and Gαi proteins dampens ligand-stimulated cAMP dynamics. This prediction was experimentally verified by measuring cAMP levels in cells under different conditions. We further predict that the direct proportionality of cAMP concentration as a function of receptor number and the inverse proportionality of cAMP concentration as a function of PDE concentration are both altered by GIV levels. Taking these results together, our model reveals that GIV acts as a tunable control valve that regulates cAMP flux after growth factor stimulation. For a given stimulus, when GIV levels are high, cAMP levels are low, and vice versa. In doing so, GIV modulates cAMP via mechanisms distinct from the two most often targeted classes of cAMP modulators, GPCRs and PDEs.

PMID:
31017840
DOI:
10.1091/mbc.E18-10-0630

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