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NCAM as a signaling receptor for GDNF family ligands

We have identified the neural cell adhesion molecule NCAM as the p135 signaling receptor for GDNF family ligands. Association of NCAM with GFR?1 was found to downregulate NCAM-mediated cell adhesion and to promote high affinity binding of GDNF to p140NCAM, resulting in rapid activation of cytoplasmic protein tyrosine kinases Fyn and FAK in cells lacking RET. GDNF stimulated Schwann cell migration and axonal growth in hippocampal and cortical neurons via binding to NCAM and activation of Fyn, but independently of RET. These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling which does not require the RET receptor.

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Karolinska Institute
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