MICROINJECTION OF ACTIVATED PHOSPHATIDYLINOSITOL-3 KINASE INDUCES PROCESS OUTGROWTH IN RAT PC12 CELLS THROUGH THE RAC-JNK SIGNAL-TRANSDUCTION PATHWAY

We have previously shown that sustained phosphatidylinositol (PI)-3 ki nase activity is necessary for neurite outgrowth of PC12 cells induced by nerve growth factor (NGF). Microinjection of a constitutively acti ve mutant of PI-3 kinase induced process formation suggesting that PI- 3 kinase is indeed involved in the neurite outgrowth. However, the pro cesses appeared to be incomplete neurites as they had very poor organi zation of F-actin and GAP43 antigen. The microtubule network was enhan ced in the process-bearing cells and process formation was inhibited b y colchicine suggesting that microtubules play an important role in pr ocess formation downstream of PI-3 kinase. These cell responses were i nhibited by dominant-negative mutants of Pac and Sek1/SAPK but not by a dominant-negative mutant Ras and PD98059, a MAP kinase kinase (MEK) inhibitor, suggesting that not the Ras-MAP kinase pathway but the Pac- Jun N-terminal kinase (JNK) pathway is involved in process formation.