Thrombopoietin inhibits nerve growth factor-induced neuronal differentiation and ERK signalling.
Thrombopoietin (TPO), a hematopoietic growth factor regulating platelet production, and its receptor (TPOR) were recently shown to be expressed in the brain where they exert proapoptotic activity. Here we used PC12 cells, an established model of neuronal differentiation, to investigate the effects of TPO on neuronal survival and differentiation. These cells expressed TPOR mRNA. TPO increased cell death in neuronally differentiated PC12 cells but had no effect in undifferentiated cells. Surprisingly, TPO inhibited nerve growth factor (NGF)-induced differentiation of PC12 cells in a dose- and time-dependent manner. This inhibition was dependent on the activity of Janus kinase-2 (JAK2). Using phospho-kinase arrays and Western blot we found downregulation of the NGF-stimulated phosphorylation of the extracellular signal-regulated kinase p42ERK by TPO with no effect on phosphorylation of Akt or stress kinases. NGF-induced phosphorylation of ERK-activating kinases, MEK1/2 and C-RAF was also reduced by TPO while NGF-induced RAS activation was not attenuated by TPO treatment. In contrast to its inhibitory effects on NGF signalling, TPO had no effect on epidermal growth factor (EGF)-stimulated ERK phosphorylation or proliferation of PC12 cells. Our data indicate that TPO via activation of its receptor-bound JAK2 delays the NGF-dependent acquisition of neuronal phenotype and decreases neuronal survival by suppressing NGF-induced ERK activity.
Samoylenko
Anatoly
A
University of Würzburg, Section of Experimental Neurosurgery, Department of Neurosurgery, Josef-Schneider-St. 11, 97080 Würzburg, Germany.
Byts
Nadiya
N
Rajalingam
Krishnaraj
K
von Ahsen
Nicolas
N
Rapp
Ulf R
UR
Ehrenreich
Hannelore
H
Sirén
Anna-Leena
AL
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D016716:PC12 Cells; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013926:Thrombopoietin / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
D004815:Epidermal Growth Factor; D013926:Thrombopoietin; D020932:Nerve Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D018631:ras Proteins