論文

査読有り
2015年5月

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

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Gary S. Ma
  • ,
  • Nicolas Aznar
  • ,
  • Nicholas Kalogriopoulos
  • ,
  • Krishna K. Midde
  • ,
  • Inmaculada Lopez-Sanchez
  • ,
  • Emi Sato
  • ,
  • Ying Dunkel
  • ,
  • Richard L. Gallo
  • ,
  • Pradipta Ghosh

112
20
開始ページ
E2602
終了ページ
E2610
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1073/pnas.1505543112
出版者・発行元
NATL ACAD SCIENCES

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, Ga-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 Gai, 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 Gai activation downstream of growth factors in a diverse array of pathophysiologic conditions.

Web of Science ® 被引用回数 : 21

リンク情報
DOI
https://doi.org/10.1073/pnas.1505543112
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25926659
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000354729500010&DestApp=WOS_CPL

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