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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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

I: Proceedings of the National Academy of Sciences, Vol. 111, Nr. 37, 2014, s. 13373-13378.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Rankin, EB, Fuh, KC, Castellini, L, Viswanathan, K, Finger, EC, Diep, AN, LaGory, EL, Kariolis, MS, Chan, A, Lindgren, D, Axelson, H, Miao, YR, Krieg, AJ & Giaccia, AJ 2014, 'Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.', Proceedings of the National Academy of Sciences, vol. 111, nr. 37, s. 13373-13378. https://doi.org/10.1073/pnas.1404848111

APA

Rankin, E. B., Fuh, K. C., Castellini, L., Viswanathan, K., Finger, E. C., Diep, A. N., ... Giaccia, A. J. (2014). Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proceedings of the National Academy of Sciences, 111(37), 13373-13378. https://doi.org/10.1073/pnas.1404848111

CBE

Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, LaGory EL, Kariolis MS, Chan A, Lindgren D, Axelson H, Miao YR, Krieg AJ, Giaccia AJ. 2014. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proceedings of the National Academy of Sciences. 111(37):13373-13378. https://doi.org/10.1073/pnas.1404848111

MLA

Vancouver

Author

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. / Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. I: Proceedings of the National Academy of Sciences. 2014 ; Vol. 111, Nr. 37. s. 13373-13378.

RIS

TY - JOUR

T1 - Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.

AU - Rankin, Erinn B

AU - Fuh, Katherine C

AU - Castellini, Laura

AU - Viswanathan, Kartik

AU - Finger, Elizabeth C

AU - Diep, Anh N

AU - LaGory, Edward L

AU - Kariolis, Mihalis S

AU - Chan, Andy

AU - Lindgren, David

AU - Axelson, Håkan

AU - Miao, Yu R

AU - Krieg, Adam J

AU - Giaccia, Amato J

PY - 2014

Y1 - 2014

N2 - Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.

AB - Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.

U2 - 10.1073/pnas.1404848111

DO - 10.1073/pnas.1404848111

M3 - Article

VL - 111

SP - 13373

EP - 13378

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 37

ER -