An unrecognized extracellular function for an intracellular adapter protein released from the cytoplasm into the tumor microenvironment.
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.
Mintz
Paul J
PJ
University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cardó-Vila
Marina
M
Ozawa
Michael G
MG
Hajitou
Amin
A
Rangel
Roberto
R
Guzman-Rojas
Liliana
L
Christianson
Dawn R
DR
Arap
Marco A
MA
Giordano
Ricardo J
RJ
Souza
Glauco R
GR
Easley
Jeffrey
J
Salameh
Ahmad
A
Oliviero
Salvatore
S
Brentani
Ricardo R
RR
Koivunen
Erkki
E
Arap
Wadih
W
Pasqualini
Renata
R
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D002352:Carrier Proteins; D009687:Nuclear Proteins