Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
Open accessAbstract
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-ras G12D 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-ras G12D -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.
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Oncogenic Ras activation has been shown to increase the expression of Spry2, providing feedback inhibition of Ras activation.
“Oncogenic Ras activation has been shown to increase the expression of Spry2, providing feedback inhibition of Ras activation (Shaw et al., 2007).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Shaw et al., 2007
In “Negative feedback signaling in development” (page not available), the paper reports that oncogenic K-ras up-regulates Spry-2 and that Spry-2 inhibits MAPK activation. It does not establish that Spry-2 inhibits activation of Ras itself; it describes possible effects at different points in the Ras/MAPK pathway, including downstream of activated K-ras. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSPRY2 negatively regulates Ras/MEK/ERK signaling and is a tumor suppressor in NSCLC in both mice and humans.
“SPRY2, in turn, negatively regulates Ras/MEK/ERK signaling and is a tumor suppressor in NSCLC in both mice (Minowada and Miller, 2004; Minowada and Miller, 2009; Shaw et al., 2007) and humans (Sutterluty et al., 2007).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Shaw et al., 2007
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- Authors
- Shaw, A. T., Meissner, A., Dowdle, J. A., Crowley, D., Magendantz, M., Ouyang, C., Parisi, T., Rajagopal, J., Blank, L. J., Bronson, R. T., Stone, J. R., Tuveson, D. A., Jaenisch, R., & Jacks, T.
- Affiliations
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Tufts University (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-03-15
- Volume
- 21
- Issue
- 6
- Pages
- 694-707
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1820943
- OpenAlex
- W2102049157
- Cited by
- 131
- References
- 49
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 9 · 2015: 11 · 2014: 6 · 2013: 9 · 2012: 7
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute (P30-CA14051)
- Damon Runyon Cancer Research Foundation
- National Cancer Institute (5K08CA111634-2, 5-U01-CA84306-06, CA14051, U01CA084306, K08CA111634, P30CA014051, P30-CA-14051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Sprouty2, KRAS G12D, lung development, lung carcinogenesis, lung branching morphogenesis, MAPK signaling, tumor suppressor, embryonic lethality, cardiovascular defects, hematopoietic defects
- MeSH terms
- Animals, Base Sequence, Female, Humans, Lung, Lung Neoplasms, Membrane Proteins, Mice, Transgenic, Pregnancy, Genes, ras, RNA, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, Germ-Line Mutation, Mice, Knockout, Gene Expression Regulation, Developmental, MAP Kinase Signaling System, Embryo Loss, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice
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