The Collagen Receptor Discoidin Domain Receptor 1b Enhances Integrin β1-Mediated Cell Migration by Interacting With Talin and Promoting Rac1 Activation.

Corina M Borza,Raymond C Harris,Roy Zent,Lynne A Lapierre,Mary Beth Browning Monroe,Matthew J Tyska,Birgit Leitinger,Marcin J Skwark,Ming-Zhi Zhang,Xiuqi Zhang,Magnus Hook,James R Goldenring,Kyle L Brown,Jens Meiler,Gema Bolas,Jose Rivera,Ambra Pozzi,Ralph T Böttcher,Markus Moser

doi:10.3389/fcell.2022.836797

Abstract

Integrins and discoidin domain receptors (DDRs) 1 and 2 promote cell adhesion and migration on both fibrillar and non fibrillar collagens. Collagen I contains DDR and integrin selective binding motifs; however, the relative contribution of these two receptors in regulating cell migration is unclear. DDR1 has five isoforms (DDR1a-e), with most cells expressing the DDR1a and DDR1b isoforms. We show that human embryonic kidney 293 cells expressing DDR1b migrate more than DDR1a expressing cells on DDR selective substrata as well as on collagen I in vitro. In addition, DDR1b expressing cells show increased lung colonization after tail vein injection in nude mice. DDR1a and DDR1b differ from each other by an extra 37 amino acids in the DDR1b cytoplasmic domain. Interestingly, these 37 amino acids contain an NPxY motif which is a central control module within the cytoplasmic domain of β integrins and acts by binding scaffold proteins, including talin. Using purified recombinant DDR1 cytoplasmic tail proteins, we show that DDR1b directly binds talin with higher affinity than DDR1a. In cells, DDR1b, but not DDR1a, colocalizes with talin and integrin β1 to focal adhesions and enhances integrin β1-mediated cell migration. Moreover, we show that DDR1b promotes cell migration by enhancing Rac1 activation. Mechanistically DDR1b interacts with the GTPase-activating protein (GAP) Breakpoint cluster region protein (BCR) thus reducing its GAP activity and enhancing Rac activation. Our study identifies DDR1b as a major driver of cell migration and talin and BCR as key players in the interplay between integrins and DDR1b in regulating cell migration.

Highlights

Cell adhesion and migration on fibrillar and non fibrillar collagens are mediated by several cell adhesion receptors such as integrins (Kechagia et al, 2019; Bourgot et al, 2020) and discoidin domain receptors (DDRs) (Itoh, 2018).DDRs are receptor tyrosine kinases that consist of two closely related members DDR1 and DDR2
We failed to detect a significant increase in Rap1 activation between DDR1a-vs DDR1b-expressing cells plated on collagen I, suggesting that an alternative mechanism is responsible for the DDR1b-mediated cell migration
We provide evidence that DDR1b regulates cell adhesion, migration and invasion in an integrin-dependent and -independent manner

Summary

Introduction

Cell adhesion and migration on fibrillar and non fibrillar collagens are mediated by several cell adhesion receptors such as integrins (Kechagia et al, 2019; Bourgot et al, 2020) and discoidin domain receptors (DDRs) (Itoh, 2018).DDRs are receptor tyrosine kinases that consist of two closely related members DDR1 and DDR2. DDRs undergo autophosphorylation on multiple tyrosine residues and initiate various downstream signaling pathways that regulate multiple cellular functions including cell adhesion and migration (Borza and Pozzi, 2014). DDR1 has emerged as an important contributor and a therapeutic target in cancer growth and metastasis (Rikova et al, 2007; Lee et al, 2019; Deng et al, 2021; Sun et al, 2021). To this end, DDR1 is upregulated in cancer cells and it is directly involved in matrix remodeling, tumor cell migration, invasion and metastasis (Lee et al, 2018; Chen et al, 2020; Lin et al, 2020; Romayor et al, 2021). The mechanism whereby DDRs mediate cell adhesion and migration and whether they promote these cell functions in an integrin-dependent and/or -independent manner is poorly understood

Objectives

Methods

Results

Conclusion