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.
机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Cavalli, V
;
Kujala, P
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机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Kujala, P
;
Klumperman, J
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机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Klumperman, J
;
Goldstein, LSB
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Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USAUniv Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Cavalli, V
;
Kujala, P
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机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Kujala, P
;
Klumperman, J
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机构:Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Klumperman, J
;
Goldstein, LSB
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Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USAUniv Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, La Jolla, CA 92093 USA