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Rap1 mediates sustained MAP kinase activation induced by nerve growth factor
1The Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201, USA.
Nature
|April 29, 1998
Summary
Nerve growth factor triggers neuronal differentiation via sustained mitogen-activated protein (MAP) kinase activation. This sustained activation relies on the small G protein Rap1, distinct from the initial Ras-dependent pathway, promoting cell growth and differentiation.
Area of Science:
- Cell Biology
- Neuroscience
- Molecular Biology
Background:
- Growth factors like nerve growth factor (NGF) and epidermal growth factor (EGF) activate mitogen-activated protein (MAP) kinase (also known as extracellular-signal-regulated kinase, ERK).
- The duration of MAP kinase activation influences cellular outcomes, with transient activation promoting proliferation and sustained activation inducing differentiation.
- PC12 cells exhibit differential responses to NGF and EGF, highlighting the importance of intracellular signaling pathways in determining cell fate.
Purpose of the Study:
- To elucidate the distinct intracellular signaling pathways mediating nerve growth factor-induced activation of MAP kinase.
- To identify the specific molecular players responsible for sustained MAP kinase activation during neuronal differentiation.
- To investigate the role of small G proteins Ras and Rap1 in coupling NGF to MAP kinase signaling.
Main Methods:
- Utilized PC12 cell models to study neuronal differentiation induced by nerve growth factor.
- Investigated the roles of small G proteins Ras and Rap1 in MAP kinase activation using biochemical assays.
- Examined the interaction between Rap1, C3G, CRK adaptor proteins, and B-Raf in the signaling cascade.
- Assessed the necessity of Rap1 for neuronal differentiation markers, including electrical excitability and gene induction.
Main Results:
- Nerve growth factor-induced MAP kinase activation involves two pathways: an initial Ras-dependent phase and a sustained Rap1-dependent phase.
- The guanine-nucleotide-exchange factor C3G and CRK adaptor proteins activate Rap1.
- Rap1 forms a stable complex with B-Raf, a key activator of MAP kinase.
- Rap1 is essential for nerve growth factor-induced electrical excitability and neuron-specific gene expression in PC12 cells.
Conclusions:
- The small G protein Rap1 plays a critical role in sustaining MAP kinase activation, driving neuronal differentiation.
- Activation of Rap1 by C3G represents a conserved mechanism for inducing sustained MAP kinase signaling in B-Raf-expressing cells.
- Understanding these distinct pathways provides insights into the molecular basis of cell fate determination by growth factors.
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