Regulation of neuronal cell death by MST1-FOXO1 signaling.
The protein kinase mammalian Sterile 20-like kinase 1 (MST1) plays a critical role in the regulation of cell death. Recent studies suggest that MST1 mediates oxidative stress-induced neuronal cell death by phosphorylating the transcription factor FOXO3 at serine 207, a site that is conserved in other FOXO family members. Here, we show that MST1-induced phosphorylation of FOXO1 at serine 212, corresponding to serine 207 in FOXO3, disrupts the association of FOXO1 with 14-3-3 proteins. Accordingly, MST1 mediates the nuclear translocation of FOXO1 in primary rat cerebellar granule neurons that are deprived of neuronal activity. We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity, and MST1 induces cell death in a FOXO1-dependent manner. Finally, we show that the MST1-regulatory, scaffold protein Nore1 is required for survival factor deprivation induced neuronal death. Collectively, these findings define MST1-FOXO1 signaling as an important link survival factor deprivation-induced neuronal cell death with implications for our understanding of brain development and neurological diseases.
Yuan
Zengqiang
Z
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lehtinen
Maria K
MK
Merlo
Paola
P
Villén
Judit
J
Gygi
Steven
S
Bonni
Azad
A
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; C074639:Foxo1 protein, rat; D017228:Hepatocyte Growth Factor