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CAM-FGF receptor interactions: a model for axonal growth
1Department of Experimental Pathology, UMDS, Guy's Hospital, London, United Kingdom.
Abstract:
A number of experimental paradigms have been used to demonstrate that NCAM, N-cadherin, and L1 stimulate axonal growth. The molecular basis of this response has been extensively studied and a range of agents that inhibit neurite outgrowth stimulated by the above CAMs, but not integrins, have now been identified. These studies pointed to the activation of a tyrosine kinase-PLCgamma cascade as being important for the neurite outgrowth responses stimulated by all three CAMs, and this was substantiated by the identification of agents that could activate the cascade and mimic the growth response. In this review we will suggest that the neurite growth response stimulated by these CAMs is mediated by activation of the fibroblast growth factor receptor (FGFR) in neurons and that this results in the recruitment and activation of PLCgamma via interactions of its SH2 domain with the activated receptor. In this context the key events downstream from activation of PLCgamma required for neurite growth appear to be the conversion of diacylglycerol (DAG) to arachidonic acid (AA) via DAG lipase activity, followed by an increased influx of calcium into the neurons. The evolutionary conservation of putative binding motifs between the above CAMs and the FGFR suggests that activation of the FGFR-PLCgamma cascade by the CAMs might involve a direct CAM-FGFR interaction. The identification of the binding motifs also allows for predictions to be made concerning whether other CAMs might directly interact with the FGFR.
Insights
Neural cell adhesion molecules (NCAMs) like N-cadherin and L1 stimulate axonal growth by activating fibroblast growth factor receptors (FGFRs) and a tyrosine kinase-PLCgamma cascade, promoting neurite outgrowth.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cell adhesion molecules (CAMs) including NCAM, N-cadherin, and L1 are known to stimulate axonal growth.
- Previous research identified inhibitors of CAM-stimulated neurite outgrowth, implicating a tyrosine kinase-PLCgamma cascade.
- Integrins were found not to be involved in this specific pathway.
Purpose of the Study:
- To propose that fibroblast growth factor receptor (FGFR) activation mediates neurite outgrowth stimulated by NCAM, N-cadherin, and L1.
- To elucidate the downstream signaling events involving PLCgamma, diacylglycerol (DAG), arachidonic acid (AA), and calcium influx.
- To investigate the potential direct interaction between CAMs and FGFRs based on conserved binding motifs.
Main Methods:
- Review of existing experimental paradigms and molecular studies on CAMs and neurite outgrowth.
- Analysis of signaling pathways, including tyrosine kinase-PLCgamma activation.
- Examination of evolutionary conservation of binding motifs between CAMs and FGFRs.
Main Results:
- Neurite outgrowth stimulated by NCAM, N-cadherin, and L1 is suggested to be mediated by FGFR activation in neurons.
- FGFR activation leads to PLCgamma recruitment and activation via SH2 domain interactions.
- Downstream events include DAG conversion to AA and subsequent calcium influx, crucial for neurite growth.
Conclusions:
- The FGFR-PLCgamma cascade is a key pathway for CAM-stimulated neurite outgrowth.
- Direct interaction between CAMs and FGFRs is proposed, supported by conserved binding motifs.
- This interaction model provides a basis for predicting other CAMs that may interact with FGFRs.