Cell proliferation

Lcking ERK Activation

Science's STKE  05 Jul 2005:
Vol. 2005, Issue 291, pp. tw243
DOI: 10.1126/stke.2912005tw243

Tapinos and Rambukkana uncovered an unexpected pathway to activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) while investigating the response of Schwann cells to long-term infection with the bacillus that causes leprosy. Damage to peripheral nerves, which involves bacterial invasion of nonmyelinating Schwann cells and leads to sensory loss, is one of the key features of leprosy. Tapinos and Rambukkana grew human Schwann cells in primary cultures and found that infection with Mycobacterium leprae stimulated their proliferation and accelerated progression through the G1 phase of the cell cycle. Gene array analysis, reverse transcription polymerase chain reaction (RT-PCR), and Western analysis indicated that expression and abundance of the G1 regulator cyclin D1 was increased 30 days after infection. Moreover, overexpression of a cyclin D1 dominant-negative mutant blocked the effects of M. leprae on G1 progression. Infected cells showed increased phosphorylation of ERK1/2 compared with controls, and transfection with a dominant-negative ERK2 protein implicated that kinase in the stimulation of cyclin D1 abundance and cell cycle progression. However, pharmacological and peptide inhibitor analysis indicated that neither the SOS-Ras-Raf-mitogen-activated protein kinase kinase (MAPK) signaling pathway, which is critical to growth factor activation of ERK1/2, nor phosphatidylinositol 3-kinase (PI3K) signaling were involved in M. leprae activation of ERK1/2. Rather, M. leprae activated ERK1/2 and thereby stimulated cell proliferation through a pathway involving protein kinase Cε (PKCε)-dependent activation of the Src family tyrosine kinase lymphoid cell kinase (p56Lck). Thus, M. leprae appears to activate a previously unknown pathway to cell proliferation and thereby to provide itself with a niche for long-term survival.

N. Tapinos, A. Rambukkana, Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad. Sci. U.S.A. 102, 9188-9193 (2005). [Abstract] [Full Text]