An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment

Paul J. Mintz, Marina Cardó-Vila, Michael G. Ozawa, Amin Hajitou, Roberto Rangel, Liliana Guzman-Rojas, Dawn R. Christianson, Marco A. Arap, Ricardo J. Giordano, Glauco R. Souza, Jeffrey Easley, Ahmad Salameh, Salvatore Oliviero, Ricardo R. Brentani, Erkki Koivunen, Wadih Arap, Renata Pasqualini

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Mammalian cell membranes provide an interface between the intracellular and extracellular compartments. It is currently thought that cytoplasmic signaling adapter proteins play no functional role within the extracellular tumor environment. Here, by selecting combinatorial random peptide libraries in tumor-bearing mice, we uncovered a direct, specific, and functional interaction between CRKL, an adapter protein [with Src homology 2 (SH2)- and SH3-containing domains], and the plexin-semaphorin-integrin domain of β1 integrin in the extracellular milieu. Through assays in vitro, in cellulo, and in vivo, we show that this unconventional and as yet unrecognized protein-protein interaction between a regulatory integrin domain (rather than a ligand-binding one) and an intracellular adapter (acting outside of the cells) triggers an alternative integrin-mediated cascade for cell growth and survival. Based on these data, here we propose that a secreted form of the SH3/SH2 adaptor protein CRKL may act as a growth-promoting factor driving tumorigenesis and may lead to the development of cancer therapeutics targeting secreted CRKL.

Original languageEnglish (US)
Pages (from-to)2182-2187
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - Feb 17 2009
Externally publishedYes


  • Cancer
  • CrkL
  • Integrin
  • Phage display

ASJC Scopus subject areas

  • General

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