Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages.
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is constitutively expressed in a variety of normal and transformed epithelial cells and plays a role in cell migration and differentiation through as yet unidentified signaling pathways. We previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DDR1a isoform in leukocyte migration through extracellular matrix. Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1 cells overexpressing these isoforms and of primary macrophages. Interestingly, collagen activation of DDR1b, but not DDR1a, further promoted phorbol ester-induced differentiation of THP-1 cells as determined by reduced cell proliferation and up-regulated expression of HLA-DR, CD11c, CD14, and CD40. Collagen activation of DDR1b also induced the recruitment and phosphorylation of Shc and subsequent phosphorylation of p38 mitogen-activated protein (MAP) kinase and its substrate ATF2. A p38 MAP kinase inhibitor, SB203580, completely inhibited DDR1b-mediated HLA-DR expression. Activation of DDR1 endogenously expressed on macrophages also up-regulated their HLA-DR expression in a p38 MAP kinase-dependent manner. Thus, DDR1b in response to collagen transduces signals that promote maturation/differentiation of HLA-DR-positive antigen-presenting cells and contributes to the development of adaptive immunity in a tissue microenvironment.
Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Wataru
W
Matsuyama
Hidenobu
H
Kamohara
Carole
C
Galligan
Michel
M
Faure
Teizo
T
Yoshimura
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D003094:Collagen / Q000378:metabolism*; D000070818:Discoidin Domain Receptors; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D006684:HLA-DR Antigens; D020033:Protein Isoforms; D011506:Proteins; D011975:Receptors, Mitogen; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate