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CAM-FGF Receptor Interactions: A Model for Axonal Growth
1Department of Experimental Pathology, UMDS, Guy's Hospital, London Bridge, London, SE1 9RT, 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 the fibroblast growth factor receptor (FGFR) pathway, leading to neurite outgrowth.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Neural cell adhesion molecules (NCAMs), including N-cadherin and L1, are known to promote axonal growth.
- Previous research identified a tyrosine kinase-PLCgamma cascade crucial for neurite outgrowth stimulated by these CAMs.
- Integrins do not mediate this specific growth response.
Purpose of the Study:
- To propose that fibroblast growth factor receptor (FGFR) activation in neurons mediates CAM-stimulated neurite outgrowth.
- To elucidate the downstream signaling events involving PLCgamma, calcium influx, and arachidonic acid production.
- To investigate the potential direct interaction between CAMs and FGFR based on conserved binding motifs.
Main Methods:
- Review of existing experimental paradigms demonstrating CAM-stimulated axonal growth.
- Analysis of molecular agents inhibiting and activating the PLCgamma cascade.
- Examination of evolutionary conserved binding motifs between CAMs and FGFR.
Main Results:
- Neurite outgrowth stimulated by NCAM, N-cadherin, and L1 is proposed to be mediated by FGFR activation.
- FGFR activation leads to PLCgamma recruitment and activation via SH2 domain interactions.
- Downstream events include DAG conversion to arachidonic acid and increased neuronal calcium influx.
Conclusions:
- The FGFR-PLCgamma cascade is central to neurite outgrowth stimulated by specific CAMs.
- A direct interaction between CAMs and FGFR is suggested by conserved binding motifs.
- This interaction model provides a framework for predicting other CAMs that may interact with FGFR.