Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection.
Humanin (HN) inhibits neuronal cell death induced by various Alzheimer's disease (AD)-related insults. It has been proposed that HN binds to a putative receptor on the cell membrane and triggers a signal transduction cascade linked to neuroprotection. Recently, it was shown that HN binds to pertussis toxin (PTX)-sensitive G protein-coupled formylpeptide receptor-like-1 molecule (FPRL-1), reduces A beta(1--42) aggregation and fibril formation, and suppresses the A beta(1--42) toxicity on mononuclear phagocytic cells [Ying, G., Iribarren, P., Zhou, Y., Gong, W., Zhang, N., Yu, Z.X., Le, Y., Cui, Y., Wang, J.M., 2004. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. Journal of Immunology 172 (11), 7078--7085.]. We here show that siRNA-mediated disruption of expression of the mouse counterpart of FPRL-1, FPR2, did not result in attenuation of HN-mediated rescue of neuronal cell death induced by AD-related insults. We simultaneously provide evidence that neuroprotection by HN in F11 cells is mediated by the STAT3 transcription factor as well as by certain tyrosine kinases. Altogether, we speculate that a receptor other than FPR2 exists that mediates HN neuroprotection in F11 neurohybrid cells.
Hashimoto
Yuichi
Y
Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Suzuki
Hiroaki
H
Aiso
Sadakazu
S
Niikura
Takako
T
Nishimoto
Ikuo
I
Matsuoka
Masaaki
M
D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D044042:Receptors, Formyl Peptide; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C481578:formyl peptide receptor 2, mouse; C427211:humanin; D019833:Genistein; D011505:Protein-Tyrosine Kinases