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

Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD
Nat Cell Biol. 2013 15 (6): 677-87

PMID: 23644467 · PMCID: PMC3794710 · DOI:10.1038/ncb2743

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 (26)

Animals Breast Neoplasms Cadherins Carcinoma, Ductal, Breast 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 Neoplasm Invasiveness Neoplasm Metastasis Phosphorylation Receptor Protein-Tyrosine Kinases Receptors, Collagen Receptors, Mitogen RNA, Small Interfering RNA Interference Signal Transduction Snail Family Transcription Factors Transcription Factors

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