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

Nandini Dey, Brian W. Howell, Pradip K. De, Donald L. Durden

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalExperimental Cell Research
Volume307
Issue number1
DOIs
StatePublished - Jul 1 2005

Keywords

  • AKT
  • CSK
  • ERK
  • FYN
  • Integrin
  • Migration
  • NGF
  • Neurite outgrowth
  • PC12 cells
  • RAC
  • RAS
  • SRC
  • YES

ASJC Scopus subject areas

  • Cell Biology

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