Sustained MAPK activation is dependent on continual NGF receptor regeneration

Dongru Qiu, Likai Mao, Shinichi Kikuchi, Masaru Tomita

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


It still remains intriguing how signal specificity is achieved when different signals are relayed by the common intracellular signal transduction pathways. A well documented example for signal specificity determination is found in rat phaeochromocytoma PC12 cells where epidermal growth factor (EGF) stimulation produces a transient mitogen-activated protein kinase (MAPK) activation and leads to cell proliferation while nerve growth factor (NGF) initiates a sustained MAPK activation and induces cell differentiation. In this simulation, we demonstrated that NGF-induced sustained MARK activation may mainly depend on continual regeneration of NGF receptors and that the presence of a small pool of surface receptors is enough to maintain a sustained MAPK activation. On the other hand, MAPK activation is not significantly sensitive to the half-life of internalized receptors and the levels of NGF-specific MAPK phosphatase MAP kinase phosphatase-3 (MKP-3), though cytoplasmic persistence of internalized NGF-bound receptors and the MKP-3 dependent feedback control also contribute to the sustaining of MAPK activation. These results are consistent with the recent experimental evidence that persistent tyrosine receptor kinase A (TrkA) activity is necessary to maintain transcription in the differentiating PC12 cells (Chang et al. 2003) and a sustained Src kinase activity is detected in response to NGF stimulation (Gatti 2003). It is suggested that sustained or transient MAPK activation induced by different growth factor and neurotrophins, which is crucial to their signaling specificity, could be satisfactorily accounted for by their specific receptor turnover kinetics rather than by the activation of specific downstream signaling cascades.

Original languageEnglish
Pages (from-to)393-403
Number of pages11
JournalDevelopment Growth and Differentiation
Issue number5
Publication statusPublished - 2004 Oct


  • E-cell
  • E-neuron
  • MAPK pathway
  • NGF
  • Receptor turnover
  • Signal specificity

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology


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