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Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET
Open accessAbstract
Significance: Here we report a fundamental and previously unknown role for the receptor tyrosine kinase AXL as a direct hypoxia-inducible transcription factor target driving the aggressive phenotype in renal clear cell carcinoma through the regulation of the SRC proto-oncogene nonreceptor tyrosine kinase and the MET proto-oncogene receptor tyrosine kinase. Of therapeutic relevance, we demonstrate that inactivation of growth arrest-specific 6 (GAS6)/AXL signaling using a soluble AXL decoy receptor reversed the invasive and metastatic phenotype of clear cell renal cell carcinoma (ccRCC) cells. Furthermore, we define a pathway by which GAS6/AXL signaling utilizes lateral activation of MET through SRC to maximize cellular invasion. Our data provide an alternative model for SRC and MET activation by GAS6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.
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“We recently identified the AXL receptor tyrosine kinase as a novel HIF target driving EMT, invasion, and metastasis in VHL-deficient and hypoxic cancer cells”
From Hypoxic control of metastasis (2016) · cites this paper as [80]
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Metadata
- Authors
- Rankin, E. B., Fuh, K. C., Castellini, L., Viswanathan, K., Finger, E. C., Diep, A. N., LaGory, E. L., Kariolis, M. S., Chan, A., Lindgren, D., Axelson, H., Miao, Y. R., Krieg, A. J., & Giaccia, A. J.
- Affiliations
- Stanford Medicine (US)
- Lund University (SE)
- University of Kansas Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-09-03
- Volume
- 111
- Issue
- 37
- Pages
- 13373-13378
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4169907
- OpenAlex
- W2079075723
- Cited by
- 269
- References
- 45
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 17 · 2023: 29 · 2022: 20 · 2021: 32 · 2020: 26 · 2019: 28 · 2018: 21 · 2017: 34 · 2016: 23 · 2015: 16 · 2014: 1
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health (CA67166)
- U.S. Public Health Service (ARO65403)
- National Cancer Institute (P01CA067166, CA088480, R37CA088480, R01CA088480, CA 67166, T32CA121940, T32CA009302)
- Army Research Office
- Topics
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- Gas6/Axl signaling, HIF-1, HIF-2, clear cell renal cell carcinoma, renal metastasis, MET oncogene, tumor invasion, therapeutic target
- MeSH terms
- Proto-Oncogene Mas, Axl Receptor Tyrosine Kinase, Endothelial PAS Domain-Containing Protein 1, Growth Arrest-Specific Protein 6, Carcinoma, Renal Cell, Enzyme Activation, Humans, Kidney Neoplasms, Models, Biological, Neoplasm Invasiveness, Phenotype, Proto-Oncogene Proteins, Signal Transduction, Cell Hypoxia, Treatment Outcome, Hepatocyte Growth Factor, src-Family Kinases, Proto-Oncogene Proteins c-met, Receptor Protein-Tyrosine Kinases, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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