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<p>RAF protein kinases are major RAS effectors that function by phosphorylating MEK. Although all three RAF isoforms share a conserved RAS binding domain and bind to GTP-loaded RAS, only ARAF uniquely enhances RAS activity. Here we uncovered the molecular basis of ARAF in regulating RAS activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF–RAS condensates tethered to the plasma membrane. These structures concentrate active RAS locally, impeding NF1-mediated negative regulation of RAS, thereby fostering receptor tyrosine kinase (RTK)-triggered RAS activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF–RAS protein condensates as distinct subcellular structures sustaining RAS activity and facilitating oncogenic RAS signaling. Targeting ARAF–RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.</p><p></p>

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Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance

  • 期刊论文

  • 发表日期：

    2025年1月27日

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  • Wen Li,
  • Xiaoxian Shi,
  • Caiwei Tan,
  • Zhaodi Jiang,
  • Mingyi Li,
  • Zhiheng Ji,
  • Jing Zhou,
  • Mengxin Luo,
  • Zuyan Fan,
  • Zhifan Ding,
  • Yue Fang,
  • Jun Sun,
  • Junjun Ding,
  • Huasong Lu,
  • Weirui Ma,
  • Wei Xie,
  • Wenjing Su

摘要

RAF protein kinases are major RAS effectors that function by phosphorylating MEK. Although all three RAF isoforms share a conserved RAS binding domain and bind to GTP-loaded RAS, only ARAF uniquely enhances RAS activity. Here we uncovered the molecular basis of ARAF in regulating RAS activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF–RAS condensates tethered to the plasma membrane. These structures concentrate active RAS locally, impeding NF1-mediated negative regulation of RAS, thereby fostering receptor tyrosine kinase (RTK)-triggered RAS activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF–RAS protein condensates as distinct subcellular structures sustaining RAS activity and facilitating oncogenic RAS signaling. Targeting ARAF–RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.