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Am J Respir Cell Mol Biol. 2018 Sep;59(3):295-305. doi: 10.1165/rcmb.2017-0419OC.

Discoidin Domain Receptor 2 Signaling Regulates Fibroblast Apoptosis through PDK1/Akt.

Author information

1
1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and.
2
2 Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Abstract

Progressive fibrosis is a complication of many chronic diseases, and collectively, organ fibrosis is the leading cause of death in the United States. Fibrosis is characterized by accumulation of activated fibroblasts and excessive deposition of extracellular matrix proteins, especially type I collagen. Extensive research has supported a role for matrix signaling in propagating fibrosis, but type I collagen itself is often considered an end product of fibrosis rather than an important regulator of continued collagen deposition. Type I collagen can activate several cell surface receptors, including α2β1 integrin and discoidin domain receptor 2 (DDR2). We have previously shown that mice deficient in type I collagen have reduced activation of DDR2 and reduced accumulation of activated myofibroblasts. In the present study, we found that DDR2-null mice are protected from fibrosis. Surprisingly, DDR2-null fibroblasts have a normal and possibly exaggerated activation response to transforming growth factor-β and do not have diminished proliferation compared with wild-type fibroblasts. DDR2-null fibroblasts are significantly more prone to apoptosis, in vitro and in vivo, than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for progression of fibrosis. We have identified a novel molecular mechanism by which DDR2 can promote the activation of a PDK1 (3-phosphoinositide dependent protein kinase-1)/Akt survival pathway, and we have found that inhibition of PDK1 can augment fibroblast apoptosis. Furthermore, our studies demonstrate that DDR2 expression is heavily skewed to mesenchymal cells compared with epithelial cells and that idiopathic pulmonary fibrosis cells and tissue demonstrate increased activation of DDR2 and PDK1. Collectively, these findings identify a promising target for fibrosis therapy.

KEYWORDS:

apoptosis; collagen; discoidin domain receptor 2; fibrosis

PMID:
29652518
PMCID:
PMC6189640
[Available on 2019-09-01]
DOI:
10.1165/rcmb.2017-0419OC
[Indexed for MEDLINE]

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