CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity

Journal Article · Fri Jul 01 04:00:00 EDT 2005 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2005.02.029· OSTI ID:20717614

Dey, Nandini ^[1]; Howell, Brian W ^[2]; De, Pradip K ^[1]; Durden, Donald L ^[1]

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1. Section of Pediatric Hematology/Oncology, Department of Pediatrics, AFLAC Cancer Center and Blood Disorders Services, Emory University School of Medicine, Atlanta, GA 30022 (United States)
2. Neurogenetics, NINDS/NIH, 10 Center Drive, Building 10/3B04, Bethesda, MD 20892 (United States)

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.

• OSTI ID: 20717614
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 307; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
GENE REGULATION
GROWTH FACTORS
INHIBITION
MONOCLINIC LATTICES
PHOSPHORYLATION
RATS
TYROSINE