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

Protein Cell. 2012 Nov;3(11):875-82. doi: 10.1007/s13238-012-2092-8. Epub 2012 Nov 10.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Movement
  • Cells, Cultured
  • Chemokine CXCL12 / metabolism*
  • Cyclic AMP / metabolism
  • Humans
  • Matrix Metalloproteinase 2 / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Phosphorylation
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction

Substances

  • Chemokine CXCL12
  • Receptors, CXCR4
  • Cyclic AMP
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Matrix Metalloproteinase 2