Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli.
Activation of extracellular signal-regulated kinase (Erk) 1/2, which plays a critical role in diverse cellular processes, including cell proliferation, is known to be mediated by the canonical Raf-mitogen-activated protein kinase kinase (MEK) kinase cascade. Alternative MEK-independent signaling pathways for Erk1/2 activation in mammalian cells are not known. During our studies ... of human primary Schwann cell response to long-term infection of Mycobacterium leprae, the causative organism of leprosy, we identified that intracellular M. leprae activated Erk1/2 directly by lymphoid cell kinase (p56Lck), a Src family member, by means of a PKCepsilon-dependent and MEK-independent signaling pathway. Activation of this signaling induced nuclear accumulation of cyclin D1, G1/S-phase progression, and continuous proliferation, but without transformation. Thus, our data reveal a previously unknown signaling mechanism of glial cell proliferation, which might play a role in dedifferentiation as well as nerve regeneration and degeneration. Our findings may also provide a potential mechanism by which an obligate intracellular bacterial pathogen like M. leprae subverts nervous system signaling to propagate its cellular niche for colonization and long-term bacterial survival.
Mesh Terms:
Blotting, Western, Bromodeoxyuridine, Cell Cycle, Cell Differentiation, Cell Nucleus, Cell Proliferation, Cell Separation, Coloring Agents, Cyclin D1, Enzyme Inhibitors, Flow Cytometry, G1 Phase, Humans, Leprosy, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), MAP Kinase Kinase 1, Microscopy, Electron, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Biological, Mycobacterium leprae, Neuroglia, Oligonucleotide Array Sequence Analysis, Peripheral Nerves, Phosphorylation, Protein Kinase C, Protein Kinase C-epsilon, Reverse Transcriptase Polymerase Chain Reaction, S Phase, Schwann Cells, Signal Transduction, Time Factors, Transfection
Blotting, Western, Bromodeoxyuridine, Cell Cycle, Cell Differentiation, Cell Nucleus, Cell Proliferation, Cell Separation, Coloring Agents, Cyclin D1, Enzyme Inhibitors, Flow Cytometry, G1 Phase, Humans, Leprosy, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), MAP Kinase Kinase 1, Microscopy, Electron, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Biological, Mycobacterium leprae, Neuroglia, Oligonucleotide Array Sequence Analysis, Peripheral Nerves, Phosphorylation, Protein Kinase C, Protein Kinase C-epsilon, Reverse Transcriptase Polymerase Chain Reaction, S Phase, Schwann Cells, Signal Transduction, Time Factors, Transfection
Proc. Natl. Acad. Sci. U.S.A.
Date: Jun. 28, 2005
PubMed ID: 15967991
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