JNK- and Rac1-dependent induction of immediate early gene pip92 suppresses neuronal differentiation.
The immediate early gene pip92 is rapidly and transiently induced by serum, basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and phobol ester, as well as various toxic stimuli. Rho GTPases, such as RhoA, Rac1 and Cdc42, have been implicated in both cytoskeletal rearrangement and cell cycle control. Rac1 and Cdc42 induce neurite outgrowth in many types of neuronal cells. A downstream effector of both Rac1 and Cdc42, p21-activated kinase (Pak1), is highly enriched in neurons. In the present study, we examined the signal transduction pathways involved in pip92 induction, focusing on the involvement of Rho family guanosine 5'-triphosphate (GTP)ases. We also examined the functional role of pip92 expression during FGF-induced neuronal differentiation in embryonic hippocampal cells. Significant and robust activation of c-Jun N-terminal Kinase (JNK), Rac1 and extracellular signal-regulated kinase (ERK) appeared to be important for pip92 induction in response to bFGF. Transient transfection of kinase-inactive MEKK7 or chemical inhibitors of JNK significantly decreased the activation of Rac1 by FGF. However, blockade of Rac1 did not affect JNK activity. Moreover, a MEK-ERK blockade did not affect Rac1 activity. Activation of JNK and Rac1 induced Pak1 activity, which could then phosphorylate and activate transcription factor Elk1. Stimulation of Pak1-dependent Elk1 was required for the bFGF-induced activation of pip92. Suppression of endogenous pip92 expression by siRNA significantly enhanced bFGF-induced neurite outgrowth, while the ectopic expression of pip92 suppressed the neurite extension. Taken together, these data suggest that neurogenic growth factor-induced expression of pip92 is critical for the regulation of neuronal differentiation, occurring through the subsequent activation of Rac1, JNK, Pak1 and Elk1.
Park
Jung Bum
JB
Department of Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Kim
Eun Joo
EJ
Yang
Eun Jin
EJ
Seo
Su Ryeon
SR
Chung
Kwang Chul
KC
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008845:Microinjections / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D013937:Thymidine Kinase / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D019038:Platelet Glycoprotein GPIb-IX Complex; D011506:Proteins; D034741:RNA, Small Interfering; C113580:U 0126; C484022:pip92 protein, rat; D013937:Thymidine Kinase; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; D020830:rac1 GTP-Binding Protein