GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation.
GIGYF2 has been reported as a candidate gene for PARK11-linked Parkinson's disease (PD). Heterozygous knockout of GIGYF2 results in neurodegeneration, suggesting important roles for GIGYF2 (Grb10 interacting GYF protein 2) in the CNS. In this study, we used novel GIGYF2 antibodies to clarify the distribution and function of GIGYF2. GIGYF2 was widely expressed, most highly in the pancreas and testis, and moderately in brain, lung, liver, kidney and spleen. In the brain, GIGYF2 was tightly associated with membrane in the S3 fraction, and localised in neuronal perikarya and proximal dendrites. Immunohistochemical analysis indicated sites of GIGYF2 localisation throughout the mouse brain, with high levels in the cerebral cortex, hippocampus, cerebellum, olfactory bulb and brainstem nuclei, but low levels in the substantia nigra and striatum. GIGYF2 was present in endosomes immunopositive for Rab4 and Grb10. Expression of GIGYF2 altered insulin-like growth factor-1 (IGF-1) receptor trafficking and enhanced IGF-1-induced extracellular signal-regulated kinase 1/2 phosphorylation, but not IGF-1 receptor or serine/threonine protein kinase Akt phosphorylation. There were no significant differences in signalling activation between cells expressing wild-type and putative PD-associated mutant GIGYF2. In PD brains, GIGYF2 did not localise to Lewy bodies. Our findings indicate a role for GIGYF2 in the regulation of signalling at endosomes, but no contribution of GIGYF2 to the pathogenesis of PD.
Higashi
Shinji
S
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawa-Higashi, Kodaira-shi, Tokyo, Japan. higashis@ncnp.go.jp
Iseki
Eizo
E
Minegishi
Michiko
M
Togo
Takashi
T
Kabuta
Tomohiro
T
Wada
Keiji
K
D000818:Animals; D001921:Brain / Q000648:ultrastructure*; D002352:Carrier Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism*; D051383:GRB10 Adaptor Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection / Q000379:methods; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism
D002352:Carrier Proteins; C478016:GIGYF2 protein, human; D016708:Synaptophysin; D051383:GRB10 Adaptor Protein; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D020695:rab4 GTP-Binding Proteins