AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network.

Nature Communications
Afnan Abu-ThuraiaJean-François Côté

Abstract

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.

References

Feb 1, 1997·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·S K Hanks, T R Polte
Dec 11, 1999·Nucleic Acids Research·M Kanehisa, S Goto
Dec 10, 2002·Science·G ManningS Sudarsanam
Nov 25, 2003·Analytical Chemistry·Alexey I NesvizhskiiRuedi Aebersold
Dec 20, 2005·The EMBO Journal·Takako SasakiErhard Hohenester
Mar 15, 2006·Trends in Cell Biology·Yi WuRaymond B Birge
Sep 2, 2006·Journal of Proteome Research·Boris ZybailovMichael P Washburn
Nov 6, 2008·Cell·Victoria Sanz-MorenoChristopher J Marshall
Jul 15, 2009·Clinical Breast Cancer·Carey K Anders, Lisa A Carey
Jun 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yingchun WangRichard L Klemke
Oct 15, 2010·Nature Biotechnology·Guomin LiuAnne-Claude Gingras
Dec 23, 2011·Clinical Science·Vyacheslav A Korshunov
Feb 9, 2012·Breast Cancer Research : BCR·Pamela J BoimelJeffrey E Segall
Mar 30, 2012·Omics : a Journal of Integrative Biology·Guangchuang YuQing-Yu He
May 11, 2012·Journal of Mammary Gland Biology and Neoplasia·Alvin T LoMina J Bissell
Jul 4, 2012·Nature Genetics·Zhenfeng ZhangTrever G Bivona
Oct 4, 2012·Annals of Oncology : Official Journal of the European Society for Medical Oncology·F Penault-Llorca, G Viale
Nov 5, 2013·Cold Spring Harbor Perspectives in Biology·Greg Lemke
Feb 22, 2014·Nature Reviews. Molecular Cell Biology·Samy LamouilleRik Derynck
Jun 7, 2014·Journal of Clinical Pathology·Timothy M D'AlfonsoSandra J Shin
Aug 16, 2014·Cancer Research·Catherine WilsonJeff Settleman
Aug 20, 2014·Cancer Research·Toni M BrandDeric L Wheeler
Oct 22, 2014·Molecular and Cellular Biology·Afnan Abu-ThuraiaJean-François Côté
Nov 8, 2014·Nucleic Acids Research·Rachael P HuntleyClaire O'Donovan

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Citations

Feb 19, 2021·Nature Communications·Suoqin JinQing Nie
May 19, 2021·Cellular Signalling·Yasaswi Gayatri Mishra, Bramanandam Manavathi
Jul 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Daria Zdżalik-BieleckaMarta Miączyńska
Aug 18, 2021·The International Journal of Biochemistry & Cell Biology·Lohit Khera, Sima Lev
Sep 24, 2021·Clinical and Experimental Medicine·Xingang WangYu Wang

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Methods Mentioned

BETA
proximity ligation assay
immunoprecipitation
nucleotide exchange
co-immunoprecipitation
co-IP
pulldown
co-IPs
bioluminescence imaging
GTPase
transfections

Software Mentioned

R
MaxQuant
MySQL
iProphet
Image J
GeneMANIA
Profiler
GraphPad Prism
SAINTexpress
ProteinProphet

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