Cited by 271Renal cell carcinoma treatmentCancer, Hypoxia, and MetabolismHepatocellular Carcinoma Treatment and Prognosis

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Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

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Rankin, Erinn B., Fuh, Katherine C., Castellini, Laura, Viswanathan, Kartik, Finger, Elizabeth C., Diep, Anh N., LaGory, Edward L., Kariolis, Mihalis S., Chan, Andy, Lindgren, David, Axelson, Håkan, Miao, Yu R., Krieg, Adam J., Giaccia, Amato J.·2014·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1404848111PMC PMC4169907

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Abstract

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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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: Rankin, Erinn B.
Fuh, Katherine C.
Castellini, Laura
Viswanathan, Kartik
Diep, Anh N.
LaGory, Edward L.
Kariolis, Mihalis S.
Lindgren, David
Axelson, Håkan
Miao, Yu R.
Krieg, Adam J.
Giaccia, Amato J.
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
DOI: 10.1073/pnas.1404848111
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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Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

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