TY - JOUR
T1 - The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis
AU - Zhang, Kun
AU - Corsa, Callie A.
AU - Ponik, Suzanne M.
AU - Prior, Julie L.
AU - Piwnica-Worms, David
AU - Eliceiri, Kevin W.
AU - Keely, Patricia J.
AU - Longmore, Gregory D.
N1 - Funding Information:
This work was supported by NIH grant P50CA94056 to the Imaging Core of the Siteman Cancer Center at Washington University, and NIH grants GM080673 and CA143868, and Susan G. Komen for the Cure KG110889 to G.D.L. C.A.C. was supported by NIH grant F31CA165729.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878615544&partnerID=8YFLogxK
U2 - 10.1038/ncb2743
DO - 10.1038/ncb2743
M3 - Article
C2 - 23644467
AN - SCOPUS:84878615544
SN - 1465-7392
VL - 15
SP - 677
EP - 687
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -