Proteolytic processing of SDF-1α by matrix metalloproteinase-2 impairs CXCR4 signaling and reduces neural progenitor cell migration

Hui Peng, Yumei Wu, Zhiyuan Duan, Pawel Ciborowski, Jialin C. Zheng

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Neural stem cells and neural progenitor cells (NPCs) exist throughout life and are mobilized to replace neurons, astrocytes and oligodendrocytes after injury. Stromal cell-derived factor 1 (SDF-1, now named CXCL12) and its receptor CXCR4, an α-chemokine receptor, are critical for NPC migration into damaged areas of the brain. Our previous studies demonstrated that immune activated and/or HIV-1-infected human monocyte-derived-macrophages (MDMs) induced a substantial increase of SDF-1 production by human astrocytes. However, matrix metalloproteinase (MMP)-2, a protein up-regulated in HIV-1-infected macrophages, is able to cleave four amino acids from the N-terminus of SDF-1, resulting in a truncated SDF-1(5-67). In this study, we investigate the diverse signaling and function induced by SDF-1α and SDF-1(5-67) in human cortical NPCs. SDF-1(5-67) was generated by incubating human recombinant SDF-1α with MMP-2 followed by protein determination via mass spectrometry, Western blotting and ELISA. SDF-1α induced time-dependent phosphorylation of extracellular signal-regulated kinases (ERK) 1/2, Akt-1, and diminished cyclic adenosine monophosphate (cAMP). In contrast, SDF-1(5-67) failed to induce these signaling. SDF-1α activation of CXCR4 induced migration of NPCs, an effect that is dependent on ERK1/2 and Akt-1 pathways; whereas SDF-1(5-67) failed to induce NPC migration. This observation provides evidence that MMP-2 may affect NPC migration through post-translational processing of SDF-1α.

Original languageEnglish (US)
Pages (from-to)875-882
Number of pages8
JournalProtein and Cell
Volume3
Issue number11
DOIs
StatePublished - Nov 19 2012

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Keywords

  • and migration
  • chemokine
  • neurogenesis
  • proteolysis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Drug Discovery
  • Cell Biology

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