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Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2602-10. doi: 10.1073/pnas.1505543112. Epub 2015 Apr 29.

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors.

Author information

1
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
2
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161.
3
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161 prghosh@ucsd.edu.

Abstract

In eukaryotes, receptor tyrosine kinases (RTKs) and trimeric G proteins are two major signaling hubs. Signal transduction via trimeric G proteins has long been believed to be triggered exclusively by G protein-coupled receptors (GPCRs). This paradigm has recently been challenged by several studies on a multimodular signal transducer, Gα-Interacting Vesicle associated protein (GIV/Girdin). We recently demonstrated that GIV's C terminus (CT) serves as a platform for dynamic association of ligand-activated RTKs with Gαi, and for noncanonical transactivation of G proteins. However, exogenous manipulation of this platform has remained beyond reach. Here we developed cell-permeable GIV-CT peptides by fusing a TAT-peptide transduction domain (TAT-PTD) to the minimal modular elements of GIV that are necessary and sufficient for activation of Gi downstream of RTKs, and used them to engineer signaling networks and alter cell behavior. In the presence of an intact GEF motif, TAT-GIV-CT peptides enhanced diverse processes in which GIV's GEF function has previously been implicated, e.g., 2D cell migration after scratch-wounding, invasion of cancer cells, and finally, myofibroblast activation and collagen production. Furthermore, topical application of TAT-GIV-CT peptides enhanced the complex, multireceptor-driven process of wound repair in mice in a GEF-dependent manner. Thus, TAT-GIV peptides provide a novel and versatile tool to manipulate Gαi activation downstream of growth factors in a diverse array of pathophysiologic conditions.

KEYWORDS:

cell-permeable GIV/Girdin peptide; fibrosis; heterotrimeric G proteins; invasion; wound healing

PMID:
25926659
PMCID:
PMC4443320
DOI:
10.1073/pnas.1505543112
[Indexed for MEDLINE]
Free PMC Article

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