Related Experiment Video

Updated: May 13, 2026

Generation, Purification, and Characterization of Cell-invasive DISC1 Protein Species
14:33

Generation, Purification, and Characterization of Cell-invasive DISC1 Protein Species

Published on: August 30, 2012

Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases

Hsueh-Liang Fu1, Anjum Sohail, Rajeshwari R Valiathan

  • 1Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.

The Journal of Biological Chemistry
|March 23, 2013
PubMed

Insights

Membrane-anchored matrix metalloproteinases (MMPs), specifically MT1-MMP, cleave discoidin domain receptor 1 (DDR1), regulating its activation by collagens. This proteolytic activity fine-tunes cell-collagen interactions at the cell-matrix interface.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Discoidin domain receptors (DDRs) are receptor tyrosine kinases crucial for cell-collagen interactions.
  • DDR activation involves collagen binding and subsequent receptor phosphorylation, initiating signal transduction.
  • The regulation of DDR activation by extracellular proteases is not fully understood.

Purpose of the Study:

  • To investigate the role of matrix metalloproteinases (MMPs) in regulating discoidin domain receptor 1 (DDR1) activation.
  • To determine which specific MMPs are involved in DDR1 cleavage and modulation of collagen-induced signaling.

Main Methods:

  • Stimulation of DDR1 with various collagens and collagenase-resistant variants.
  • Analysis of DDR1 cleavage and phosphorylation in the presence of different membrane-anchored and secreted MMPs.
  • N-terminal sequencing and mutational analysis to identify cleavage sites.
  • Inhibition of metalloproteinases to assess endogenous DDR1 shedding and activation.

Main Results:

  • Membrane-anchored collagenases MT1-, MT2-, and MT3-matrix metalloproteinase (MMP) cleave DDR1, reducing collagen I- and IV-induced phosphorylation.
  • This cleavage occurs independently of ligand degradation and specifically targets the extracellular juxtamembrane region.
  • Secreted MMPs (MMP-1, MMP-13) and GPI-anchored MT4- and MT6-MMP do not affect DDR1 cleavage or activation.
  • MT1-MMP mediates constitutive shedding of DDR1 in breast cancer cells and regulates collagen-induced activation.

Conclusions:

  • Membrane-anchored collagenases, particularly MT1-MMP, play a significant role in regulating DDR1 cleavage and activation.
  • Proteolytic processing of DDR1 by specific MMPs provides a novel mechanism for controlling cell-collagen interactions.
  • These findings highlight the importance of the cell-matrix interface in modulating receptor tyrosine kinase signaling.

More Related Videos

2D and 3D Matrices to Study Linear Invadosome Formation and Activity12:25

2D and 3D Matrices to Study Linear Invadosome Formation and Activity

Published on: June 2, 2017

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex07:17

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

Related Concept Videos

Role of Matrix Metalloproteases in Degradation of ECM01:23

Role of Matrix Metalloproteases in Degradation of ECM

Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult body.
A...
Degenerative Disc Disease ll: Pathophysiology01:23

Degenerative Disc Disease ll: Pathophysiology

The symptoms of degenerative disc disease arise from a combination of mechanical compression, vascular compromise, and biochemical inflammation, which together disrupt nerve function and produce pain.Mechanical CompressionDisc degeneration reduces height and elasticity, predisposing to herniation of the nucleus pulposus, a major cause of radicular pain. Herniations may be protrusion (bulging with intact annulus), extrusion (nucleus extends beyond disc but remains connected), or sequestration...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
Cancer Cell Migration through Invadopodia01:35

Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that  degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However, invadopodia can...