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PMID: 23644467 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.

Nature cell biology ·Vol. 15 ·No. 6 ·2013-06-00 ·Pages 677-87

Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD

Abstract

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.

MeSH Terms
Animals Breast Neoplasms/metabolism,pathology Cadherins/biosynthesis Carcinoma, Ductal, Breast/metabolism,pathology Cell Line, Tumor Cell Movement Cell Proliferation Discoidin Domain Receptors Epithelial-Mesenchymal Transition Female HEK293 Cells Humans Mice Mice, Inbred BALB C Mitogen-Activated Protein Kinase 1/metabolism Neoplasm Invasiveness Neoplasm Metastasis Phosphorylation RNA Interference RNA, Small Interfering Receptor Protein-Tyrosine Kinases/genetics,metabolism Receptors, Collagen/metabolism Receptors, Mitogen/genetics,metabolism Signal Transduction Snail Family Transcription Factors Transcription Factors/metabolism
Chemicals
Cadherins RNA, Small Interfering Receptors, Collagen Receptors, Mitogen SNAI1 protein, human Snai1 protein, mouse Snail Family Transcription Factors Transcription Factors Discoidin Domain Receptors Receptor Protein-Tyrosine Kinases MAPK1 protein, human Mitogen-Activated Protein Kinase 1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zhang Kun
BRIGHT Institute, Washington University, St Louis, Missouri 63110, USA.
Corsa Callie A
Ponik Suzanne M
Prior Julie L
Piwnica-Worms David
Eliceiri Kevin W
Keely Patricia J
Longmore Gregory D
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2743
Published
2013-06-00
Epub
2013-00-05
Pages
677-87
Language
English
Region
England
NLM ID
100890575
PMCID
PMC3794710
Subset
IM
Grants
NCI NIH HHS · P50 CA094056 · United States
NCI NIH HHS · U54 CA143868 · United States
NIGMS NIH HHS · GM080673 · United States
NCI NIH HHS · CA143868 · United States
NCI NIH HHS · P50CA94056 · United States
NCI NIH HHS · F31 CA165729 · United States
NIEHS NIH HHS · T32 ES007015 · United States
NIGMS NIH HHS · R01 GM080673 · United States
NCI NIH HHS · F31CA165729 · United States
External Links
PubMed source DOI: 10.1038/ncb2743 PMC Full Text View journal details
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