Distinct neurite outgrowth signaling pathways converge on ERK activation

Several distinct classes of proteins positively regulate axonal growth; some of these are known to activate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade, at least in nonneuronal cells. We have found that N-cadherin, as well as laminin (LN) and basic fibroblast growth factor (bFGF), can activate ERK in embryonic chick retinal neurons. Additionally, adhesion of retinal neurons to LN or N-cadherin substrates induced a redistribution of ERK from the cytoplasm toward the plasma membrane. Neurite outgrowth induced by bFGF, LN, or N-cadherin was strongly inhibited by treatment with inhibitors of ERK kinase activation, but not by an inhibitor of p38 MAPK. We conclude (1) that N-cadherin and LN can activate ERK in retinal neurons and (2) that activation of ERK is required for full neurite outgrowth induced by these proteins. Our results suggest that ERK activation is one point of convergence for signaling pathways generated by a variety of axon growth inducers.