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.
Tapinos
Nikos
N
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, Bronk Building Room 501, 1230 York Avenue, New York, NY 10021, USA.
Rambukkana
Anura
A
D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D004396:Coloring Agents / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D007918:Leprosy / Q000382:microbiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D009166:Mycobacterium leprae / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010525:Peripheral Nerves / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D012583:Schwann Cells / Q000201:enzymology* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D004396:Coloring Agents; D004791:Enzyme Inhibitors; D019938:Cyclin D1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D001973:Bromodeoxyuridine