Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5629
Title: An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment.
Authors: P. J., Mintz
M., CARDÓ VILA OZAWA
A., Hajitou
R., Rangel
L., GUZMAN ROJAS
D. R., Christianson
M., AA ARAP
R. J., Giordano
G. R., Souza
J., Easley
Salameh, Ahmad
Oliviero, Salvatore 
R. R., Brentani
E., Koivunen
W., Arap
R., Pasqualini
Issue Date: 2009
Project: None 
Journal: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Abstract: 
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 beta(1) 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.
Description: 
19801
URI: http://hdl.handle.net/20.500.12779/5629
ISSN: 0027-8424
DOI: 10.1073/pnas.0807543105
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