MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

  • Guoxiang Jin
  • Fengju Zhang
  • Hoi Leong Xavier Wong
  • Baohua Liu
  • Kathryn S. E. Cheah
  • Xinguang Liu
  • Cornelia Mauch
  • Depei Liu
  • Zhongjun Zhou

Detail(s)

Original languageEnglish
Pages (from-to)2281-2293
Journal / PublicationEMBO Journal
Volume30
Issue number11
Publication statusPublished - 1 Jun 2011
Externally publishedYes

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. © 2011 European Molecular Biology Organization.

Research Area(s)

  • B-cell differentiation, Dll1, MT1-MMP, Notch signalling

Citation Format(s)

MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development. / Jin, Guoxiang; Zhang, Fengju; Chan, Kui Ming; Xavier Wong, Hoi Leong; Liu, Baohua; Cheah, Kathryn S. E.; Liu, Xinguang; Mauch, Cornelia; Liu, Depei; Zhou, Zhongjun.

In: EMBO Journal, Vol. 30, No. 11, 01.06.2011, p. 2281-2293.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal