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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84518 |
| Date | 03 April 2023 |
| Creators | Borza, Corina M., Bolas, Gema, Zhang, Xiuqi, Browning Monroe, Mary Beth, Zhang, Ming-Zhi, Meiler, Jens, Skwark, Marcin J., Harris, Raymond C., Lapierre, Lynne A., Goldenring, James R., Hook, Magnus, Rivera, Jose, Brown, Kyle L., Leitinger, Birgit, Tyska, Matthew J., Moser, Markus, Böttcher, Ralph T., Zent, Roy, Pozzi, Ambra |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2296-634X, 836797 |
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