title: MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development.
abstract: Notch signalling controls the differentiation of haematopoietic progenitor cells (HPCs). Here, we show that loss of membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP14), a cell surface protease expressed in bone marrow stromal cells (BMSCs), increases Notch signalling in HPCs and specifically impairs B-lymphocyte development. When co-cultured with BMSCs in vitro, HPCs differentiation towards B lymphocytes is significantly compromised on MT1-MMP-deficient BMSCs and this defect could be completely rescued by DAPT, a specific Notch signalling inhibitor. The defective B-lymphocyte development could also be largely rescued by DAPT in vivo. MT1-MMP interacts with Notch ligand Delta-like 1 (Dll1) and promotes its cleavage on cell surface in BMSCs. Ectopic MT1-MMP cleaves Dll1 and results in diminished Notch signalling in co-cultured cells. In addition, recombinant MT1-MMP cleaves a synthetic Dll1 peptide at the same site where MT1-MMP cleaves Dll1 on the cell surface. Our data suggest that MT1-MMP directly cleaves Dll1 on BMSCs to negatively regulate Notch signalling to specifically maintain normal B-cell development in bone marrow.
authors.affiliation: Department of Biochemistry, Center for Reproduction, Development and Growth, The University of Hong Kong, Pok Fu Lam, Hong Kong.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.forename: Fengju
authors.initials: F
authors.lastname: Zhang
authors.forename: Kui Ming
authors.initials: KM
authors.lastname: Chan
authors.forename: Hoi Leong
authors.initials: HL
authors.lastname: Xavier Wong
authors.forename: Baohua
authors.initials: B
authors.lastname: Liu
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Xinguang
authors.initials: X
authors.lastname: Liu
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Depei
authors.initials: D
authors.lastname: Liu
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C507096:Mmp14 protein, mouse; D051880:Receptors, Notch; D053511:Matrix Metalloproteinase 14