Network topology determines dynamics of the mammalian MAPK1,2 signaling network: Bifan motif regulation of C-Raf and B-Raf isoforms by FGFR and MC1R

Melissa Muller, Mandri Obeyesekere, Gordon B. Mills, Prahlad T. Ram

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Activation of the fibroblast growth factor (FGFR) and melanocyte stimulating hormone (MC1R) receptors stimulates B-Raf and C-Raf isoforms that regulate the dynamics of MAPK1,2 signaling. Network topology motifs in mammalian cells include feed-forward and feedback loops and bifans where signals from two upstream molecules integrate to modulate the activity of two downstream molecules. We computationally modeled and experimentally tested signal processing in the FGFR/MC1R/B-Raf/C-Raf/MAPK1,2 network in human melanoma cells; identifying 7 regulatory loops and a bifan motif. Signaling from FGFR leads to sustained activation of MAPK1,2, whereas signaling from MC1R results in transient activation of MAPK1,2. The dynamics of MAPK activation depends critically on the expression level and connectivity to C-Raf, which is critical for a sustained MAPK1,2 response. A partially incoherent bifan motif with a feedback loop acts as a logic gate to integrate signals and regulate duration of activation of the MAPK signaling cascade. Further reducing a 106-node ordinary differential equations network encompassing the complete network to a 6-node network encompassing rate-limiting processes sustains the feedback loops and the bifan, providing sufficient information to predict biological responses.

Original languageEnglish (US)
Pages (from-to)1393-1403
Number of pages11
JournalFASEB Journal
Volume22
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Keywords

  • Computational modeling
  • Melanoma
  • Proteomics

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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