title: Role of plasma membrane localization of the scaffold protein JSAP1 during differentiation of cerebellar granule cell precursors.
abstract: We previously reported that the scaffold protein c-Jun NH₂-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) functions in cerebellar granule cell precursors (GCPs) to promote their cell-cycle exit and differentiation. In this study, we used immunocytochemistry to examine the subcellular distribution of JSAP1 in proliferating cultured GCPs. We found that when stimulated with fibroblast growth factor-2 (FGF-2), a factor that promotes GCP differentiation through JNK and extracellular signal-regulated kinase (ERK) signaling, JSAP1 translocated to the plasma membrane and colocalized with activated JNK and ERK. In transfected cells expressing a constitutively activated FGF receptor (FGFR), JSAP1 and the activated FGFR colocalized at the plasma membrane with not only activated but also unphosphorylated and inactive JNK and ERK. These colocalizations did not occur when a mutant JSAP1 lacking the JNK-binding domain was substituted for wild-type JSAP1. Biochemical analyses of transfected cells showed that activated FGFR increased JSAP1's affinity for JNK and ERK and that JSAP1 enhanced FGFR-induced JNK and ERK activation. Collectively, these results suggest that when stimulated by FGFR, JSAP1 translocates to the plasma membrane, where it recruits JNK and ERK and facilitates their activation, leading to the differentiation of cerebellar GCPs.
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tokiharu
authors.initials: T
authors.lastname: Sato
authors.forename: Anir
authors.initials: A
authors.lastname: Enkhbat
authors.forename: Katsuji
authors.initials: K
authors.lastname: Yoshioka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C403619:Mapk8ip3 protein, mouse; D009419:Nerve Tissue Proteins; D016222:Fibroblast Growth Factor 2; D048056:Mitogen-Activated Protein Kinase 9; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8