Dear Khan,

The attached publication covers the answer to your question.

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

Kun Zhang,

Callie A. Corsa,

Suzanne M. Ponik,

Julie L. Prior,

David Piwnica-Worms,

Kevin W. Eliceiri,

Patricia J. Keely

& Gregory D. Longmore

Affiliations

Contributions

Corresponding author

Nature Cell Biology

15,

677–687

(2013)

doi:10.1038/ncb2743

Received

20 January 2013

Accepted

28 March 2013

Published online

05 May 2013

Article tools

Citation

Reprints

Rights & permissions

Article metrics

Abstract

Abstract•

References•

Author information•

Supplementary information

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.

http://www.nature.com/ncb/journal/v15/n6/full/ncb2743.html?WT.ec_id=NCB-201306

 2-https://books.google.ps/books?id=dLJLcq1qrtYC&pg=PA60&lpg=PA60&dq=Can+degraded+collagen-I+activate+DDR2&source=bl&ots=jBpihUp2Ts&sig=Vou8G_m4OHPu2HhVpopoPl7X2ZA&hl=en&sa=X&ved=0ahUKEwjkppbxg_PJAhVGJHIKHQBxCvYQ6AEINDAE#v=onepage&q=Can%20degraded%20collagen-I%20activate%20DDR2&f=false

3-DDR2 receptor promotes MMP-2–mediated proliferation

and invasion by hepatic stellate cells 

Elvira Olaso,1 Kazuo Ikeda,1 Francis J. Eng,1 Lieming Xu,1 Li-Hsien Wang,2

Hsin Chieh Lin,2 and Scott L. Friedman1

1Division of Liver Diseases and Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

2Regeneron Pharmaceuticals, Tarrytown, New York, USA

Address correspondence to: Scott L. Friedman, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave, Room 1170F,

New York, New York 10029, USA. Phone: (212) 659-9501; Fax: (212) 849-2574; E-mail: [email protected].

Elvira Olaso’s present address is: Biomedical Research and Technological Development Institute, INBIOMED Foundation,

San Sebastian Technology Park, Gipuzkoa, Spain.

Lieming Xu’s present address is: Shanghai University of TCM, Shanghai, China.

Received for publication January 30, 2001, and accepted in revised form September 14, 2001.

Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in

stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell

lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.

J. Clin. Invest. 108:1369–1378 (2001). DOI:10.1172/JCI200112373

Discussion

Our data demonstrate that expression of DDR2 accompanies activation of stellate cells in vivo and in culture and is regulated by extracellular matrix composition. Moreover, DDR2 is restricted to stellate cells among resident liver cell types, consistent with the observation that DDR2 expression is confined to mesenchymal cell lineages (14). Furthermore, the findings provide evidence of a positive feedback loop in which induction of DDR2 leads to enhanced cell proliferation and MMP-2 activity, with accelerated degradation of a collagen type IV-containing matrix. This could allow for replacement of the hepatic subendothelial matrix by fibrillar collagen, which in turn is the ligand for DDR2. The data further explain how interstitial collagen in the pericellular milieu directly provokes stellate cell activation through specific receptor signaling by DDR2.

4- Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2*

Elvira Olaso‡§,

Juan-Pablo Labrador¶,‖**,

LiHsien Wang‡,

Kazuo Ikeda‡,

Francis J. Eng‡,

Rudiger Klein¶,

David H. Lovett§§,

Hsin Chieh Lin‡ and

Scott L. Friedmanদ

+Author Affiliations

From the ‡Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, the ¶Developmental Biology Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany, the ‖Department of Immunology and Oncology, Centro Nacional de Biotecnologı́a, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid Campus de Cantoblanco E-28049, Madrid, Spain, ‡Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York 10591, and the §§Department of Medicine and the Veterans Affairs Medical Center, University of California, San Francisco, California 94121

Next Section

Abstract

Discoidin domain receptor 2 (DDR2) is a tyrosine kinase receptor expressed in mesenchymal tissues, the ligand of which is fibrillar collagen. We have compared DDR2 signaling in skin fibroblasts derived from DDR2−/− and DDR2+/− mice. Proliferation of DDR2−/−fibroblasts was significantly decreased compared with DDR2+/− cells. DDR2−/− fibroblasts exhibited markedly impaired capacity to migrate through a reconstituted basement membrane (Matrigel) in response to a chemotactic stimulus, which correlated with diminished matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography and diminished MMP-2 transcription of a minimal MMP-2 promoter. In contrast, a lack of DDR2 had no effect on cell motility or α-smooth muscle actin or vinculin expression. Additionally, expression of type I collagen was greatly reduced in DDR2−/− cells. Stable reconstitution of either wild-type DDR2 or constitutively active chimeric DDR2 in DDR2−/−cells by retroviral infection restored cell proliferation, migration through a reconstituted basement membrane (Matrigel), and MMP-2 levels to those of DDR2+/−fibroblasts. These data establish a role for DDR2 in critical events during wound repair.

Cutaneous wound healing is a dynamic interactive response involving re-epithelialization and formation of granulation tissue (1). Both of these processes require tightly controlled remodeling of the wound matrix, in turn reflecting the net outcome of synthesis and degradation of extracellular matrix (ECM)1components. In the healing wound, this matrix is composed of both fibrillar (i.e.types I and III) and non-fibrillar (i.e.types IV and VI) collagens. Whereas fibrillar collagens comprise the bulk of parenchymal scar tissue, non-fibrillar collagens within basement membranes play critical roles in epithelial cell polarity and function (2, 3).

http://www.jbc.org/content/277/5/3606.full

Hoping this will be helpful,

Rafik

Much obliged Dr. Rafik.