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

Amélie Juin (1) , Julie Di Martino (1) , Birgit Leitinger , Elodie Henriet (1) , Anne-Sophie Gary (1) , Lisa Paysan (1) , Jeremy Bomo , Georges Baffet (2) , Cécile Gauthier-Rouvière (3) , Jean Rosenbaum (1) , Violaine Moreau (1) , Frédéric Saltel (1)

1 Physiopathologie du cancer du foie
2 Irset - Institut de recherche en santé, environnement et travail
3 CRBM - Centre de recherche en Biologie Cellulaire

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.

Domaines: Sciences du Vivant [q-bio]

Amélie Juin, Julie Di Martino, Birgit Leitinger, Elodie Henriet, Anne-Sophie Gary, et al.. Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway.. Journal of Cell Biology, 2014, 207 (4), pp.517-33. ⟨10.1083/jcb.201404079⟩. ⟨hal-01118481⟩