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PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation

Lauren Foltz1, Juan Palacios-Moreno2, Makenzie Mayfield1

  • 1Division of Biological Sciences, Center for Biomolecular Structure and Dynamics, and Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT 59812.

Molecular Biology of the Cell
|July 30, 2020
PubMed

Insights

The scaffold protein PAG1 regulates SRC family kinase (SFK) localization, impacting cell fate decisions after receptor tyrosine kinase (RTK) activation. Disrupting PAG1 function impairs neuronal differentiation by altering SFK signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Receptor tyrosine kinases (RTKs) activate common downstream pathways, yet elicit distinct cellular responses.
  • The role of scaffold proteins like PAG1 in mediating differential RTK signaling and cell fate is not fully understood.

Purpose of the Study:

  • To investigate the hypothesis that PAG1 regulates SRC family kinase (SFK) signaling to influence cell fate decisions following RTK activation.
  • To determine how PAG1 affects SFK localization and activity in response to RTK signaling.

Main Methods:

  • Generated a neuroblastoma cell line expressing a cytoplasm-localized PAG1 fragment (PAG1TM-).
  • Assessed SFK activity, cell proliferation, and differentiation responses to RTK signaling (TRKA, RET, EGFR, KIT).
  • Analyzed the intracellular localization of FYN and LYN kinases using microscopy.

Main Results:

  • PAG1TM- cells showed increased active SFKs and growth rate.
  • These cells were unresponsive to TRKA and RET signaling-induced neuronal differentiation but retained EGFR and KIT responses.
  • Activated FYN and LYN kinases were sequestered within multivesicular bodies (MVBs) in PAG1TM- cells, disrupting differentiation.

Conclusions:

  • PAG1 directs SFK intracellular localization, controlling their activity.
  • PAG1 is crucial for mediating RTK signaling that induces neuronal differentiation.
  • Altered PAG1 function disrupts SFK localization, leading to impaired cell fate decisions.

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