title: DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation.
abstract: DDR1 (discoidin domain receptor tyrosine kinase 1) kinase s highly expressed in a variety of human cancers and occasionally mutated in lung cancer and leukemia. It is now clear that aberrant signaling through the DDR1 receptor is closely associated with various steps of tumorigenesis, although little is known about the molecular mechanism(s) underlying the role of DDR1 in cancer. Besides the role of DDR1 in tumorigenesis, we previously identified DDR1 kinase as a transcriptional target of tumor suppressor p53. DDR1 is functionally activated as determined by its tyrosine phosphorylation, in response to p53-dependent DNA damage. In this study, we report the characterization of the Notch1 protein as an interacting partner of DDR1 receptor, as determined by tandem affinity protein purification. Upon ligand-mediated DDR1 kinase activation, Notch1 was activated, bound to DDR1, and activated canonical Notch1 targets, including Hes1 and Hey2. Moreover, DDR1 ligand (collagen I) treatment significantly increased the active form of Notch1 receptor in the nuclear fraction, whereas DDR1 knockdown cells show little or no increase of the active form of Notch1 in the nuclear fraction, suggesting a novel intracellular mechanism underlying autocrine activation of wild-type Notch signaling through DDR1. DDR1 activation suppressed genotoxic-mediated cell death, whereas Notch1 inhibition by a γ-secretase inhibitor, DAPT, enhanced cell death in response to stress. Moreover, the DDR1 knockdown cancer cells showed the reduced transformed phenotypes in vitro and in vivo xenograft studies. The results suggest that DDR1 exerts prosurvival effect, at least in part, through the functional interaction with Notch1.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Hyung-Gu
authors.initials: HG
authors.lastname: Kim
authors.forename: So-Young
authors.initials: SY
authors.lastname: Hwang
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D000070819:Discoidin Domain Receptor 1; D004789:Enzyme Activation / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024042:Collagen Type I; D004151:Dipeptides; D000070819:Discoidin Domain Receptor 1; D018398:Homeodomain Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D016159:Tumor Suppressor Protein p53; C405693:HEY2 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C495901:TP53 protein, human; C078493:HES1 protein, human; C092030:DDR1 protein, human