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Journal of Cell Science 115, 1883-1893 (2002)
© 2002 The Company of Biologists Limited

Research Article

Leukotriene D4 activates MAPK through a Ras-independent but PKC{epsilon}-dependent pathway in intestinal epithelial cells

Sailaja Paruchuri1, Bengt Hallberg2, Maria Juhas1, Christer Larsson3 and Anita Sjölander*,1

1 Division of Experimental Pathology, Department of Laboratory Medicine, Lund University, University Hospital Malmö, SE-205 02 Malmö
2 Department of Cell and Molecular Biology, University of Umeå, SE-901 87 Umeå, Sweden
3 Division of Molecular Medicine, Department of Laboratory Medicine, Lund University, University Hospital Malmö, SE-205 02 Malmö

* Author for correspondence (e-mail: anita.sjolander{at}exppat.mas.lu.se )

Accepted 30 January 2002

We have recently shown that leukotriene D4 (LTD4) increases cell survival in intestinal epithelial cells. Here we report and explore the complementary finding that LTD4 also enhances proliferation in these cells. This proliferative response was approximately half of that induced by epidermal growth factor (EGF) and its required activation of protein kinase C (PKC), Ras and the mitogen-activated protein kinase (MAPK) Erk-1/2. EGF also activated Erk-1/2 in these cells; however the EGF-receptor inhibitor PD153035 did not affect the LTD4-induced activation of Erk-1/2. In addition, LTD4 did not induce phosphorylation of the EGF receptor, nor did pertussis toxin (PTX) block EGF-induced activation of Erk-1/2, thus refuting a possible crosstalk between the receptors. Furthermore, LTD4-induced, but not EGF-induced, activation of Erk-1/2 was sensitive to PTX, PKC inhibitors and downregulation of PKC{epsilon}. A definite role for PKC{epsilon} in LTD4-induced stimulation of Erk-1/2 was documented by the inability of LTD4 to activate Erk-1/2 in cells transfected with either the regulatory domain of PKC{epsilon} (an isoform specific dominant-negative inhibitor) or a kinase-dead PKC{epsilon}. Although Ras and Raf-1 were both transiently activated by LTD4, only Raf-1 activation was abolished by abrogation of the PKC signal. Furthermore, the LTD4-induced activation of Erk-1/2 was unaffected by transfection with dominant-negative N17 Ras but blocked by transfection with kinase-dead Raf-1. Consequently, LTD4 regulates the proliferative response by a distinct Ras-independent, PKC{epsilon}-dependent activation of Erk-1/2 and a parallel Ras-dependent signaling pathway.

Key words: Leukotriene D4, Ras, Protein kinase C, Raf-1, MAPK, Intestinal epithelial cell proliferation




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© The Company of Biologists Ltd 2002