title: A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration.
abstract: Regulation of cell migration is an important step for the development of branching tubule morphogenesis in collagen gel. Here, we showed that discoidin domain receptor (DDR) 1a/b inhibited collagen-induced tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 1/3 and cell migration triggered by alpha2beta1-integrin. Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2. Expression of catalytically inactive SHP-2 in DDR1-transfected cells restored the tyrosine phosphorylation of Stat3 and cell migration. We demonstrated that the Src homology-2 (SH2)-SH2 and phosphotyrosyl phosphatase (PTP) domains of SHP-2 were responsible for interaction with DDR1 and that both tyrosine phosphorylation sites 703 and 796 of DDR1 were essential for it to bind with SHP-2. Mutation of tyrosine 703 or 796 of DDR1 abolished the ability of DDR1 to inhibit the tyrosine phosphorylation of Stat1 and Stat3 and restored collagen-induced cell migration and hepatocyte growth factor-induced branching tubulogenesis in collagen gel. Together, these results demonstrate that SHP-2 is required for the DDR1-induced suppression of Stat1 and Stat3 tyrosine phosphorylation, cell migration, and branching tubulogenesis.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 701, Taiwan.
authors.forename: Chau-Zen
authors.initials: CZ
authors.lastname: Wang
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Su
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Hsu
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D004285:Dogs; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney; D051379:Mice; D008954:Models, Biological; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D038982:Integrin alpha2beta1; D047908:Intracellular Signaling Peptides and Proteins; D011975:Receptors, Mitogen; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse