How does the NGF signaling pathway work?
the NGF molecule works by binding to a high-affinity tyrosine kinase receptor, TrkA, found on the plasma membrane of target cells. NG binding causes TrkA receptors to dimerize and the intrinsic tyrosine kinase activity of each receptor then phosphorylates its partner receptor. Phosphorylated TrkA receptors trigger the ras casade, resulting in the activation of multiple protein kinases. Some of these kinases translocate to the nucleus to activate transcriptional activatiors such as CREB. This ras-based component of the NGF pathway is primarily responsible for inducing and maintaining differentiations of NGF-sensitive neurons.
Phosphorylaton of TrkA also causes this receptor to stimulate the activity of phospholipase C, which increases production of IP3 and DAG. IP3 induces release of Ca from the endoplamic reticulum, and DAG activates PKC. These two second messengers apear to target many of the same downstream effectors as ras.
Finally, activation of TrkA receptors also causes activation of other protein kinases that inhibit cell death. This patway, therefore, primarily mediates the NGF-dependent survival of sympathetic and sensory neurons
