Proteolytic processing of SDF-1α by matrix metalloproteinase-2 impairs CXCR4 signaling and reduces neural progenitor cell migration.
10.1007/s13238-012-2092-8
- Author:
Hui PENG
1
;
Yumei WU
;
Zhiyuan DUAN
;
Pawel CIBOROWSKI
;
Jialin C ZHENG
Author Information
1. Laboratory of Neuroimmunology and Regenerative Therapy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Publication Type:Journal Article
- MeSH:
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;
metabolism;
Phosphorylation;
Proteolysis;
Proto-Oncogene Proteins c-akt;
metabolism;
Receptors, CXCR4;
metabolism;
Signal Transduction
- From:
Protein & Cell
2012;3(11):875-882
- CountryChina
- Language:English
-
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.
