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 Rafmitogen-activated protein kinase kinase (MEK) kinase cascade. Alternative MEK-independent signaling path...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-06, Vol.102 (26), p.9188-9193 |
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Sprache: | eng |
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Zusammenfassung: | 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 Rafmitogen-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 PKCε-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. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0501196102 |