Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors.
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.
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Gary S
GS
Ma
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Nicolas
N
Aznar
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Nicholas
N
Kalogriopoulos
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Krishna K
KK
Midde
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Inmaculada
I
Lopez-Sanchez
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Emi
E
Sato
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093; and.
Ying
Y
Dunkel
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.
Richard L
RL
Gallo
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.
Pradipta
P
Ghosh
D000818:Animals; D057846:Cell-Penetrating Peptides / Q000378:metabolism* / Q000627:therapeutic use; D031541:Fluorescence Resonance Energy Transfer; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005818:Genetic Engineering / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C502451:CCDC88A protein, human; D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D019204:GTP-Binding Proteins
cell-permeable GIV/Girdin peptide; fibrosis; heterotrimeric G proteins; invasion; wound healing