AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network.
Adaptor Proteins, Signal Transducing
/ genetics
Cell Line, Tumor
Cell Movement
Focal Adhesions
/ genetics
Humans
Neoplasm Invasiveness
Neoplasms
/ genetics
Paxillin
/ genetics
Phosphorylation
Protein-Tyrosine Kinases
/ genetics
Proto-Oncogene Proteins
/ genetics
Receptor Protein-Tyrosine Kinases
/ genetics
Signal Transduction
Axl Receptor Tyrosine Kinase
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
16
08
2018
accepted:
28
06
2020
entrez:
19
7
2020
pubmed:
19
7
2020
medline:
20
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32681075
doi: 10.1038/s41467-020-17415-x
pii: 10.1038/s41467-020-17415-x
pmc: PMC7368075
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
NEDD9 protein, human
0
PXN protein, human
0
Paxillin
0
Proto-Oncogene Proteins
0
PEAK1 protein, human
EC 2.7.10.1
Protein-Tyrosine Kinases
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Axl Receptor Tyrosine Kinase
0
AXL protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3586Subventions
Organisme : CIHR
ID : MOP-142425
Pays : Canada
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