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PNAS 102 (26): 9188-9193

Copyright © 2005 by the National Academy of Sciences.


CELL BIOLOGY

Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli

Nikos Tapinos, and Anura Rambukkana *

Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, Bronk Building Room 501, 1230 York Avenue, New York, NY 10021

Edited by Stanley Falkow, Stanford University, Stanford, CA, and approved May 11, 2005

Received for publication February 11, 2005.

Abstract: 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 PKC{epsilon}-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.

Key Words: cell signaling • cell cycle • peripheral nerve • human • Mycobacterium leprae


Author contributions: N.T. and A.R. designed research; N.T. performed research; N.T. and A.R. analyzed data; and A.R. and N.T. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: Erk, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; DNM, dominant-negative mutant; PI3K, phosphatidylinositol 3-kinase; MEKI, MEK inhibitor; PI3KI, PI3K inhibitor; PKCI, PKC pan-inhibitor; Lck, lymphoid cell kinase; LckI, Lck inhibitor.

* To whom correspondence should be addressed. E-mail: rambuka{at}imap.rockefeller.edu.

© 2005 by The National Academy of Sciences of the USA


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