CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity |
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Authors: | Dey Nandini Howell Brian W De Pradip K Durden Donald L |
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Institution: | Section of Pediatric Hematology/Oncology, Department of Pediatrics, AFLAC Cancer Center and Blood Disorders Services, Emory University School of Medicine, Atlanta, GA 30022, USA. |
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Abstract: | Src family kinases are involved in transducing growth factor signals for cellular differentiation and proliferation in a variety of cell types. The activity of all Src family kinases (SFKs) is controlled by phosphorylation at their C-terminal 527-tyrosine residue by C-terminal SRC kinase, CSK. There is a paucity of information regarding the role of CSK and/or specific Src family kinases in neuronal differentiation. Pretreatment of PC12 cells with the Src family kinase inhibitor, PP1, blocked NGF-induced activation of SFKs and obliterated neurite outgrowth. To confirm a role for CSK and specific isoforms of SFKs in neuronal differentiation, we overexpressed active and catalytically dead CSK in the rat pheochromocytoma cell line, PC12. CSK overexpression caused a profound inhibition of NGF-induced activation of FYN, YES, RAS, and ERK and inhibited neurite outgrowth, NGF-stimulated integrin-directed migration and blocked the NGF-induced conversion of GDP-RAC to its GTP-bound active state. CSK overexpression markedly augmented the activation state of AKT following NGF stimulation. In contrast, kinase-dead CSK augmented the activation of FYN, RAS, and ERK and increased neurite outgrowth. These data suggest a distinct requirement for CSK in the regulation of NGF/TrkA activation of RAS, RAC, ERK, and AKT via the differential control of SFKs in the orchestration of neuronal differentiation. |
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Keywords: | SFKs Src family kinases NGF nerve growth factor CSK C-terminal Src kinase PBD p21 binding domain SH2 SRC homology-2 domain WT-CSK wild type CSK KD-CSK kinase-dead CSK |
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