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Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.
Kothiwale S, Borza CM, Lowe EW, Pozzi A, Meiler J
(2015) Drug Discov Today 20: 255-61
MeSH Terms: Animals, Discoidin Domain Receptors, Drug Discovery, Humans, Molecular Structure, Protein Kinase Inhibitors, Protein Structure, Tertiary, Receptor Protein-Tyrosine Kinases, Receptors, Mitogen
Show Abstract · Added October 27, 2014
Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable.
Copyright © 2014 Elsevier Ltd. All rights reserved.
1 Communities
4 Members
0 Resources
9 MeSH Terms
Discoidin domain receptors in disease.
Borza CM, Pozzi A
(2014) Matrix Biol 34: 185-92
MeSH Terms: Animals, Cell Movement, Cell Proliferation, Discoidin Domain Receptor 1, Discoidin Domain Receptors, Extracellular Matrix, Fibrosis, Humans, Inflammation, Mice, Receptor Protein-Tyrosine Kinases, Receptors, Mitogen, Signal Transduction
Show Abstract · Added February 24, 2014
Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling. While activation of DDRs by extracellular matrix collagens is required for normal development and tissue homeostasis, aberrant activation of these receptors following injury or in disease is detrimental. The availability of mice lacking DDRs has enabled us to identify key roles played by these receptors in disease initiation and progression. DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury, while DDR2 contributes to osteoarthritis. Furthermore, both DDRs have been implicated in cancer progression. Yet the mechanisms whereby DDRs contribute to disease progression are poorly understood. In this review we highlight the mechanisms whereby DDRs regulate two important processes, namely inflammation and tissue fibrosis. In addition, we discuss the challenges of targeting DDRs in disease. Selective targeting of these receptors requires understanding of how they interact with and are activated by extracellular matrix, and whether their cellular function is dependent on or independent of receptor kinase activity.
Copyright © 2014 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
0 Communities
2 Members
1 Resources
13 MeSH Terms
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
(2013) Nat Cell Biol 15: 677-87
MeSH Terms: 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, RNA Interference, RNA, Small Interfering, Receptor Protein-Tyrosine Kinases, Receptors, Collagen, Receptors, Mitogen, Signal Transduction, Snail Family Transcription Factors, Transcription Factors
Show Abstract · Added July 31, 2013
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.
1 Communities
0 Members
0 Resources
26 MeSH Terms
A new target for therapy in squamous cell carcinoma of the lung.
Ohashi K, Pao W
(2011) Cancer Discov 1: 23-4
MeSH Terms: Animals, Carcinoma, Non-Small-Cell Lung, Discoidin Domain Receptors, Humans, Lung Neoplasms, Receptor Protein-Tyrosine Kinases, Receptors, Mitogen
Show Abstract · Added March 24, 2014
Investigators report the identification of novel somatic mutations in the DDR2 kinase gene in squamous cell carcinoma of the lung. Cellular, biochemical, and human data suggest that tumor cells harboring DDR2 mutations have increased sensitivity to existing tyrosine kinase inhibitors, providing rationale for clinical trials of agents that inhibit DDR2 kinase in the disease.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Endo180 binds to the C-terminal region of type I collagen.
Thomas EK, Nakamura M, Wienke D, Isacke CM, Pozzi A, Liang P
(2005) J Biol Chem 280: 22596-605
MeSH Terms: Alkaline Phosphatase, Animals, Blotting, Northern, Blotting, Western, COS Cells, Cell Adhesion, Cell Differentiation, Cell Line, Cell Separation, Collagen, Collagen Type I, DNA, Complementary, Down-Regulation, Drug Combinations, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Fibroblasts, Fibronectins, Flow Cytometry, Gene Expression Profiling, Glycine, Humans, Laminin, MAP Kinase Signaling System, Models, Molecular, Molecular Sequence Data, Peptides, Phenotype, Placenta, Protein Binding, Protein Structure, Tertiary, Proteoglycans, RNA Interference, RNA, Small Interfering, Rats, Receptors, Mitogen, Recombinant Fusion Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Time Factors, Transfection, ras Proteins
Show Abstract · Added February 24, 2014
Type I collagen is a fibril-forming heterotrimer composed of two alpha1 and one alpha2 chains and plays a crucial role in cell-matrix adhesion and cell differentiation. Through a comprehensive differential display screening of oncogenic ras target genes, we have shown that the alpha1 chain of type I collagen (col1a1) is markedly down-regulated by the ras oncogene through the mitogen-activated protein kinase pathway. Although ras-transformed cells are no longer able to produce and secrete endogenous collagen, they can still adhere to exogenous collagen, suggesting that the cells express a collagen binding factor(s) on the cell surface. When the region of col1a1 encompassing the C-terminal glycine repeat and C-prodomain (amino acids 1000-1453) was affinity-labeled with human placental alkaline phosphatase, the secreted trimeric fusion protein could bind to the surface of Ras-transformed cells. Using biochemical purification followed by matrix-assisted laser desorption/ionization mass spectrometry analysis, we identified this collagen binding factor as Endo180 (uPARAP, CD280), a member of the mannose receptor family. Ectopic expression of Endo180 in CosE5 cells followed by in situ staining and quantitative binding assays confirmed that Endo180 indeed recognizes and binds to placental alkaline phosphatase. The interaction between Endo180 and the C-terminal region of type I collagen appears to play an important role in cell-matrix adhesion.
0 Communities
1 Members
0 Resources
41 MeSH Terms