Axl is essential for VEGF-A-dependent activation of PI3K/Akt.

The EMBO Journal
Guo-Xiang Ruan, Andrius Kazlauskas

Abstract

Herein, we report that vascular endothelial growth factor A (VEGF-A) engages the PI3K/Akt pathway by a previously unknown mechanism that involves three tyrosine kinases. Upon VEGF-A-dependent activation of VEGF receptor-2 (VEGFR-2), and subsequent TSAd-mediated activation of Src family kinases (SFKs), SFKs engage the receptor tyrosine kinase Axl via its juxtamembrane domain to trigger ligand-independent autophosphorylation at a pair of YXXM motifs that promotes association with PI3K and activation of Akt. Other VEGF-A-mediated signalling pathways are independent of Axl. Interfering with Axl expression or function impairs VEGF-A- but not bFGF-dependent migration of endothelial cells. Similarly, Axl null mice respond poorly to VEGF-A-induced vascular permeability or angiogenesis, whereas other agonists induce a normal response. These results elucidate the mechanism by which VEGF-A activates PI3K/Akt, and identify previously unappreciated potential therapeutic targets of VEGF-A-driven processes.

References

Sep 1, 1996·Molecular and Cellular Biology·J A ForsytheG L Semenza
Oct 15, 1996·Proceedings of the National Academy of Sciences of the United States of America·D S OryR C Mulligan
Sep 12, 1997·The Journal of Biological Chemistry·P McCloskeyE T Liu
Mar 14, 2000·Current Opinion in Cell Biology·J P WhiteheadD E James
Nov 30, 2000·Trends in Cardiovascular Medicine·M G MelaragnoB C Berk
Oct 5, 2001·Cellular Signalling·N ItoL Claesson-Welsh
Dec 13, 2001·Science's STKE : Signal Transduction Knowledge Environment·T Matsumoto, L Claesson-Welsh
Dec 3, 2002·FEBS Letters·Isabelle SixKenneth Walsh
Jun 5, 2003·Nature Medicine·Napoleone FerraraJennifer LeCouter
Sep 19, 2003·Trends in Biochemical Sciences·Michael J CrossLena Claesson-Welsh
Jun 18, 2005·The EMBO Journal·Taro MatsumotoLena Claesson-Welsh
Aug 3, 2005·The Journal of Clinical Investigation·Eric AckahWilliam C Sessa
Sep 9, 2005·Frontiers in Bioscience : a Journal and Virtual Library·Nader Rahimi
Oct 19, 2005·Cancer Research·Sacha J HollandJames B Lorens
Mar 4, 2006·Science·Yingfeng QiaoPhilip A Cole
Mar 21, 2006·Vascular Pharmacology·Nilesh M PandyaDev D Santani
Apr 22, 2006·The EMBO Journal·Eunok Im, Andrius Kazlauskas
Apr 25, 2006·Nature Reviews. Molecular Cell Biology·Anna-Karin OlssonLena Claesson-Welsh
Oct 6, 2006·The New England Journal of Medicine·Philip J RosenfeldUNKNOWN MARINA Study Group
Oct 6, 2006·The New England Journal of Medicine·David M BrownUNKNOWN ANCHOR Study Group
Aug 9, 2007·The Journal of Biological Chemistry·Eunok Im, Andrius Kazlauskas
Oct 20, 2007·Nature Protocols·Michael S RogersRobert J D'Amato
May 9, 2008·The New England Journal of Medicine·Robert S Kerbel
Aug 7, 2008·Cardiovascular Research·Greg A KnockPhilip I Aaronson

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Citations

Jun 13, 2012·The Journal of Experimental Medicine·Zuyue SunLena Claesson-Welsh
Jul 20, 2012·Molecular Biology of the Cell·Reetta VirtakoivuJohanna Ivaska
Jul 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lars StangenbergDiane Mathis
Nov 20, 2014·Future Medicinal Chemistry·Chao DingYuyang Jiang
Nov 12, 2015·Journal of Medicinal Chemistry·Samuel H MyersAsier Unciti-Broceta
Feb 27, 2015·International Journal of Cancer. Journal International Du Cancer·Andreas K A GaumannGeorg Breier
Mar 19, 2013·Experimental Cell Research·Mariona Graupera, Michael Potente
Sep 25, 2012·European Journal of Medical Genetics·Gerarda Cappuccio, Nicola Brunetti-Pierri
Dec 12, 2012·Journal of Internal Medicine·L Claesson-Welsh, M Welsh
May 27, 2015·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Lavina AhmedLars A Akslen
Mar 5, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Linlin TangXiuzhen Han
Jan 17, 2015·Annual Review of Immunology·Carla V RothlinSourav Ghosh
Apr 27, 2016·Cellular and Molecular Life Sciences : CMLS·Fei GaoPayaningal R Somanath
Jul 28, 2016·Nature Reviews. Molecular Cell Biology·Michael SimonsLena Claesson-Welsh
Jan 11, 2017·British Journal of Cancer·Carl M GayLauren Averett Byers
Jul 8, 2016·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·X LiA Liu
May 30, 2017·Laboratory Investigation; a Journal of Technical Methods and Pathology·Naoya FujinoRose A Maciewicz
Oct 27, 2018·Histochemistry and Cell Biology·Rajender NandigamaErik Henke
Mar 9, 2019·Journal of Cellular Biochemistry·Zuo Pei-YuanLiu Cheng-Yun
Jan 9, 2015·Nature Reviews. Cancer·Douglas K GrahamH Shelton Earp
Apr 14, 2019·Cardiovascular Research·Lucy McShanePasquale Maffia
May 30, 2019·Physiological Reviews·Nina WettschureckStefan Offermanns
Aug 17, 2019·International Journal of Molecular Sciences·Francesco MocciaGermano Guerra
Dec 4, 2019·Journal of Biomedical Materials Research. Part a·Martin HellerWalburgis Brenner
May 14, 2019·Oncotarget·Mai Tanaka, Dietmar W Siemann
Feb 13, 2018·Oncology Letters·Guoan ZhangWen Cui
Feb 14, 2017·Genes & Cancer·Noushin NabaviLuciano Mutti

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