Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion.
Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.
Jagadeeswaran
Ramasamy
R
Department of Medicine, University of Chicago Cancer Research Center, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
Surawska
Hanna
H
Krishnaswamy
Soundararajan
S
Janamanchi
Varalakshmi
V
Mackinnon
A Craig
AC
Seiwert
Tanguy Y
TY
Loganathan
Sivakumar
S
Kanteti
Rajani
R
Reichman
Trevor
T
Nallasura
Vidya
V
Schwartz
Stuart
S
Faoro
Leonardo
L
Wang
Yi-Ching
YC
Girard
Luc
L
Tretiakova
Maria S
MS
Ahmed
Salman
S
Zumba
Osvaldo
O
Soulii
Lioubov
L
Bindokas
Vytas P
VP
Szeto
Livia L
LL
Gordon
Gavin J
GJ
Bueno
Raphael
R
Sugarbaker
David
D
Lingen
Mark W
MW
Sattler
Martin
M
Krausz
Thomas
T
Vigneswaran
Wickii
W
Natarajan
Viswanathan
V
Minna
John
J
Vokes
Everett E
EE
Ferguson
Mark K
MK
Husain
Aliya N
AN
Salgia
Ravi
R
D000818:Animals; D049109:Cell Proliferation; D018628:Gene Dosage; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000208:ethnology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D034622:RNA Interference
D051419:Paxillin; D019253:Proto-Oncogene Proteins c-bcl-2; D019859:Proto-Oncogene Proteins c-met