Objective: Increased matrix stiffness is sensed by the collagen-binding receptor tyrosine kinase discoidin domain receptor 1 (DDR1). We have previously shown that DDR1 stimulates a positive feedback loop to increase its own expression in vascular smooth muscle cells (VSMCs). The transcriptional co-factors YAP/TAZ are stiffness sensing molecules that have not previously been investigated in DDR1 signaling. Here, we test the hypothesis that DDR1 signals through YAP/TAZ to auto-regulate its own expression.
Approach And Results: We used vascular smooth muscle cells (VSMCs) from wild-type and DDR1 knockout mice stimulated with collagen and/or substrates of different stiffness. We show that DDR1 controls YAP/TAZ nuclear localization and activity, whereas knockdown of YAP/TAZ attenuates DDR1 expression. In response to increased substrate stiffness, collagen stimulation, or RhoA activation, YAP/TAZ translocate to the nucleus and bind to chromatin. Finally, collagen stimulation promotes increased YAP/TAZ association with the Ddr1 promoter.
Conclusions: These findings reveal the mechanism by which DDR1 regulates YAP/TAZ activity which can then mediate positive feedback regulation of DDR1 expression by promoting transcription of the DDR1 gene.
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http://dx.doi.org/10.1016/j.matbio.2022.05.004 | DOI Listing |
Bioorg Chem
December 2024
Department of pharmacy, Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province 210008, China. Electronic address:
Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase superfamily, which mainly activates downstream signaling pathways through binding to collagen. The abnormal expression of DDR1 is closely related to the occurrence and development of various tumors, and it is one of the potential targets for molecular targeted therapy. At present, specific antibodies and selective small molecule inhibitors against DDR1 have been approved for Phase I clinical trials.
View Article and Find Full Text PDFFASEB J
December 2024
Sarcoma Biology Laboratory, Department of Orthopedic Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
Osteosarcoma is the most common type of bone cancer. Some patients eventually develop recurrent or metastatic diseases and treatment options are extremely limited. Discoidin domain receptor 1 (DDR1) is a unique collagen-activated tyrosine kinase that participates in various human diseases, including cancer.
View Article and Find Full Text PDFCancer Lett
February 2025
Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. Electronic address:
Breast cancer is the predominant malignancy with the majority of cases are characterized as HR+/HER2-subtype. Although cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have shown remarkable efficacy in treating this subtype when combined with endocrine therapy, the development of resistance to these inhibitors remains a significant clinical obstacle. Hence, there is an urgent need to explore innovative therapies and decipher the underlying mechanisms of resistance to CDK4/6i.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China.
Human periodontal ligament cells (hPDLCs) express matrix metalloproteinases (MMPs), a group of enzymes responsible for the destruction of most extracellular matrix proteins in dental tissues, especially MMP-1, MMP-2, and MMP-13. Exploring the regulatory mechanism of MMPs is crucial for understanding external root resorption (ERR), one of the most severe complications, along with substantial loss of dental tissue, induced by trauma, pulpal infection, tooth bleaching, and orthodontic treatment, etc. Discoidin domain receptor 1 (DDR1), a cell surface receptor binding to collagen, has the potential to regulate the expression of MMP-1, MMP-2, and MMP-13, but the mechanism remains unclear.
View Article and Find Full Text PDFCell Death Dis
November 2024
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Cervical cancer is a leading cause of cancer-related death among women and its recurrence and metastasis poses challenges to treatment. Discoidin domain receptor 1 (DDR1) was associated with cellular migration and invasion in several types of cancers. However, its function in cervical cancer is still unclear.
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