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Molecular and Cellular Biology, March 2000, p. 1931-1946, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Nerve Growth Factor Activation of the Extracellular
Signal-Regulated Kinase Pathway Is Modulated by Ca2+
and Calmodulin
Joaquim
Egea,1
Carme
Espinet,1
Rosa M.
Soler,1
Sandra
Peiró,2
Nativitat
Rocamora,3 and
Joan X.
Comella1,*
Grup de Neurobiologia Molecular, Departament de
Ciències Mèdiques Bàsiques, Facultat de Medicina,
Universitat de Lleida, 25198 Lleida,1 and
Department of Cell Biology, Institut d'Investigacions
Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de
Medicina, Universitat de Barcelona, 08036 Barcelona,2 and Laboratori de Biologia
Molecular, Institut Català d'Oncologia (ICO), 08907 L'Hospitalet de Llobregat,3 Catalonia, Spain
Received 16 April 1999/Returned for modification 12 May
1999/Accepted 8 December 1999
Nerve growth factor is a member of the neurotrophin family of
trophic factors that have been reported to be essential for the
survival and development of sympathetic neurons and a subset of sensory
neurons. Nerve growth factor exerts its effects mainly by interaction
with the specific receptor TrkA, which leads to the activation of
several intracellular signaling pathways. Once activated, TrkA also
allows for a rapid and moderate increase in intracellular calcium
levels, which would contribute to the effects triggered by nerve growth
factor in neurons. In this report, we analyzed the relationship of
calcium to the activation of the Ras/extracellular signal-regulated
kinase pathway in PC12 cells. We observed that calcium and calmodulin
are both necessary for the acute activation of extracellular
signal-regulated kinases after TrkA stimulation. We analyzed the
elements of the pathway that lead to this activation, and we observed
that calmodulin antagonists completely block the initial Raf-1
activation without affecting the function of upstream elements, such as
Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli
that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is
necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a
calcium-dependent manner.
*
Corresponding author. Mailing address: Grup de
Neurobiologia Molecular, Departament de Ciències Mèdiques
Bàsiques, Universitat de Lleida, Avda. Rovira Roure, 44, 25198 Lleida, Spain. Phone: 34-973-702.414. Fax: 34-973-702.426. E-mail:
joan.comella{at}cmb.udl.es.
Molecular and Cellular Biology, March 2000, p. 1931-1946, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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