Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis.
Somatic activation of Ras occurs frequently in human cancers, including one-third of lung cancers. Activating Ras mutations also occur in the germline, leading to complex developmental syndromes. The precise mechanism by which Ras activation results in human disease is uncertain. Here we describe the phenotype of a mouse engineered to harbor a germline oncogenic K-rasG12D mutation. This mouse exhibits early embryonic lethality due to a placental trophoblast defect. Reconstitution with a wild-type placenta rescues the early lethality, but mutant embryos still succumb to cardiovascular and hematopoietic defects. In addition, mutant embryos demonstrate a profound defect in lung branching morphogenesis associated with striking up-regulation of the Ras/mitogen-activated protein kinase (MAPK) antagonist Sprouty-2 and abnormal localization of MAPK activity within the lung epithelium. This defect can be significantly suppressed by lentiviral short hairpin RNA (shRNA)-mediated knockdown of Sprouty-2 in vivo. Furthermore, in the context of K-rasG12D-mediated lung tumorigenesis, Sprouty-2 is also up-regulated and functions as a tumor suppressor to limit tumor number and overall tumor burden. These findings indicate that in the lung, Sprouty-2 plays a critical role in the regulation of oncogenic K-ras, and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease.
Shaw
Alice T
AT
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston 02114, USA.
Meissner
Alexander
A
Dowdle
James A
JA
Crowley
Denise
D
Magendantz
Margaret
M
Ouyang
Chensi
C
Parisi
Tiziana
T
Rajagopal
Jayaraj
J
Blank
Leah J
LJ
Bronson
Roderick T
RT
Stone
James R
JR
Tuveson
David A
DA
Jaenisch
Rudolf
R
Jacks
Tyler
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D020964:Embryo Loss / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012313:RNA; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse