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Optogenetic Delineation of Receptor Tyrosine Kinase Subcircuits in PC12 Cell Differentiation

John S Khamo1, Vishnu V Krishnamurthy1, Qixin Chen2

  • 1Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Cell Chemical Biology
|January 1, 2019
PubMed

Insights

Researchers used optogenetics to activate TrkA signaling, revealing that Y490 and Y785 contribute additively to PC12 cell differentiation via the extracellular-signal-regulated kinase pathway.

Area of Science:

  • Cellular signaling and neuroscience research.

Background:

  • Nerve growth factor (NGF) signaling involves high-affinity (TrkA) and low-affinity (p75NTR) receptors.
  • Both receptors activate the extracellular-signal-regulated kinase (ERK) pathway, but their distinct roles require further elucidation.
  • PC12 cell differentiation is a model system for studying NGF-induced neuronal development.

Purpose of the Study:

  • To investigate the specific roles of TrkA signaling subcircuits in PC12 cell differentiation.
  • To develop and utilize an optogenetic system for precise TrkA activation, independent of NGF.
  • To identify key tyrosine residues in TrkA that mediate differentiation through the ERK pathway.

Main Methods:

  • Development of an optogenetic TrkA system activated by light.
  • Utilizing tyrosine mutants of optogenetic TrkA.
  • Employing pathway-specific pharmacological inhibition.
  • Assessing PC12 cell differentiation.

Main Results:

  • Optogenetic TrkA activation enabled specific signaling studies, bypassing NGF and p75NTR confounding effects.
  • Tyrosine residues Y490 and Y785 were identified as critical for TrkA-mediated PC12 cell differentiation.
  • These residues contribute additively to differentiation via the ERK pathway.

Conclusions:

  • The optogenetic approach provides a powerful tool to dissect receptor-mediated signaling pathways.
  • Specific TrkA tyrosine residues play additive roles in NGF-induced cellular differentiation.
  • This methodology can be broadly applied to study other signaling cascades.
Keywords:
ERKPC12 cell differentiationPLCγTrkA signaling subcircuitsY490Y785nerve growth factoroptogenetics

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