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The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways

Chuan-Ming Xie1, Mingjia Tan2, Xiao-Tong Lin3

  • 1Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Institute of Hepatobiliary Surgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China.

Cell Reports
|March 14, 2019
PubMed

Insights

The E3 ligase FBXW7 targets SHOC2 for degradation, inhibiting oncogenic RAS-ERK and mTORC1 pathways. This SHOC2 regulation impacts cell proliferation and is linked to pancreatic cancer survival and lung cancer mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • FBXW7 is a tumor suppressor targeting oncogenic pathways.
  • RAS-ERK and mTORC1 are key oncogenic signaling pathways.
  • The regulation of these pathways by FBXW7 remains unclear.

Purpose of the Study:

  • To investigate the role of FBXW7 in regulating RAS-ERK and mTORC1 pathways.
  • To identify substrates of FBXW7 involved in these oncogenic pathways.

Main Methods:

  • Identified SHOC2 as a FBXW7 substrate.
  • Investigated SHOC2 phosphorylation and ubiquitylation.
  • Assessed the interaction between SHOC2, Raptor, and mTORC1.
  • Analyzed SHOC2 expression and mutations in cancer patient data.

Main Results:

  • FBXW7 targets phosphorylated SHOC2 for ubiquitylation and degradation, terminating RAS-MAPK signaling.
  • SHOC2 inhibits mTORC1 by binding to Raptor, inducing autophagy.
  • SHOC2 overexpression in pancreatic cancer correlates with poor survival.
  • Gain-of-function SHOC2 mutations are found in lung cancer.

Conclusions:

  • FBXW7-mediated SHOC2 degradation is a critical mechanism controlling RAS-ERK and mTORC1 pathways.
  • SHOC2 acts as a crucial node, mediating negative cross-talk between RAS-ERK and mTORC1.
  • SHOC2 dysregulation contributes to cancer development and progression.
Keywords:
FBXW7MAPKRAS-RAF-ERKRaptorSCF E3 ligaseSHOC2autophagycell proliferationmTORubiquitylation and degradation

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