NEURITE OUTGROWTH STIMULATED BY THE TYROSINE KINASE INHIBITOR HERBIMYCIN-A REQUIRES ACTIVATION OF TYROSINE KINASES AND PROTEIN-KINASE-C

Activation of tyrosine kinases is established as an important mechanis m for controlling growth cone motility and neurite outgrowth. We have tested the effects of a range of tyrosine kinase inhibitors on neurite outgrowth from postnatal day 4 cerebellar granule cells cultured over confluent monolayers of 3T3 fibroblasts. The only agent that had any effect was herbimycin A, which stimulated neurite outgrowth. The respo nse is shown to be attributable to a direct effect of this tyrosine ki nase inhibitor on neurones. The neurite outgrowth response to herbimyc in A was inhibited by two other tyrosine kinase inhibitors, which on t heir own did not affect neurite outgrowth. The data suggest that the r esponse to herbimycin A reflects either a direct or indirect activatio n of one or more protein tyrosine kinases. Independent signalling even ts downstream from tyrosine kinase activation underlying the neurite o utgrowth response to herbimycin A include increased activity of protei n kinase C and calcium influx into neurones through both N- and L-type calcium channels.