title: The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus.
abstract: Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Su-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Guerrero
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Wassef
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Mehta
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Yen
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000602199:HNG peptide; D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C427211:humanin; D050822:Cytokine Receptor gp130; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases
keywords: AKT; ERK1/2; Gerotarget; STAT3; humanin; signaling pathway