Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway

J Cell Biol. 2014 Nov 24;207(4):517-33. doi: 10.1083/jcb.201404079.


Accumulation of type I collagen fibrils in tumors is associated with an increased risk of metastasis. Invadosomes are F-actin structures able to degrade the extracellular matrix. We previously found that collagen I fibrils induced the formation of peculiar linear invadosomes in an unexpected integrin-independent manner. Here, we show that Discoidin Domain Receptor 1 (DDR1), a collagen receptor overexpressed in cancer, colocalizes with linear invadosomes in tumor cells and is required for their formation and matrix degradation ability. Unexpectedly, DDR1 kinase activity is not required for invadosome formation or activity, nor is Src tyrosine kinase. We show that the RhoGTPase Cdc42 is activated on collagen in a DDR1-dependent manner. Cdc42 and its specific guanine nucleotide-exchange factor (GEF), Tuba, localize to linear invadosomes, and both are required for linear invadosome formation. Finally, DDR1 depletion blocked cell invasion in a collagen gel. Altogether, our data uncover an important role for DDR1, acting through Tuba and Cdc42, in proteolysis-based cell invasion in a collagen-rich environment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton
  • Actins / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Cell Line, Tumor
  • Collagen Type I / metabolism*
  • Collagenases / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Dipeptides / pharmacology
  • Discoidin Domain Receptor 1
  • Extracellular Matrix / metabolism
  • Humans
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Neoplasm Invasiveness / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • cdc42 GTP-Binding Protein / metabolism*


  • Actins
  • Adaptor Proteins, Vesicular Transport
  • Collagen Type I
  • Cytoskeletal Proteins
  • DNMBP protein, human
  • Dipeptides
  • Matrix Metalloproteinase Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • RNA, Small Interfering
  • SH3PXD2A protein, human
  • DDR1 protein, human
  • Discoidin Domain Receptor 1
  • Receptor Protein-Tyrosine Kinases
  • Collagenases
  • cdc42 GTP-Binding Protein