Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade.
Maturation of dendritic cells (DCs) is critical for their ability to stimulate resting naive T cells in primary immune responses. Previous studies demonstrated that collagen, such as type I collagen, could facilitate DC maturation; however, the basis of collagen-mediated DC maturation remains unclear. Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor constitutively expressed in a variety of epithelial cells, including tumor cells, and is inducible in leukocytes. In this study, we evaluated the role of DDR1 in DC maturation using human monocyte-derived DCs. Two DDR1 isoforms, DDR1a and DDR1b, were expressed in both immature and mature DCs. Activation of DDR1 on immature DCs resulted in their partial maturation; however, DDR1 activation markedly amplified TNF-alpha- and LPS-induced phenotypic and functional maturation of DCs through activation of p38 mitogen-activated protein kinase (MAPK), suggesting the involvement of DDR1b in this process. Activation of DDR1b on differentiated DDR1b-overexpressing THP-1 cells or DDR1 on mature DCs induced the formation of TNFR associated factor 6 (TRAF6)/TGF-beta-activated kinase 1 binding protein 1beta/p38alpha MAPK complex and p38alpha autophosphorylation. Transfection of differentiated DDR1b-overexpressing THP-1 cells with dominant negative TRAF6 completely abrogated DDR1b-mediated p38 MAPK phosphorylation, indicating a critical role of TRAF6 in DDR1b-mediated p38 MAPK activation. Taken together, our data suggest that DDR1b-collagen interaction augments the maturation of DCs in a tissue microenvironment through a unique TRAF6/TGF-beta-activated kinase 1 binding protein 1beta/p38alpha MAPK signaling cascade and contributes to the development of adaptive immune responses.
D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D000070818:Discoidin Domain Receptors; D000070821:Discoidins; D006801:Humans; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000378:metabolism*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D046911:Macromolecular Substances; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D011975:Receptors, Mitogen / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D000070818:Discoidin Domain Receptors; D000070821:Discoidins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases; D046911:Macromolecular Substances; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D015800:Protozoan Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human