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LCK-Mediated RIPK3 Activation Controls Double-Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by

Sung-Min Hwang1,2, Yu-Jin Ha1,3, Gi-Bang Koo1,3

  • 1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 26, 2022
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) regulates T cell development and suppresses thymic tumors. RIPK3 deficiency promotes thymic lymphoma by upregulating ERK signaling, highlighting a RIPK3-PP2A-ERK axis for therapy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Biology

Background:

  • Receptor-interacting protein kinase 3 (RIPK3) regulates necroptotic cell death.
  • RIPK3 silencing in cancer suggests tumor suppressor roles, but mechanisms are unclear.
  • RIPK3's role in T cell development and cancer is not fully understood.

Purpose of the Study:

  • Investigate RIPK3's function in CD4+ CD8+ double-positive (DP) thymocyte homeostasis.
  • Determine RIPK3's role in thymic tumor development and survival.
  • Elucidate the molecular mechanism linking RIPK3 to thymic lymphoma.

Main Methods:

  • Analysis of RIPK3-deficient mice, including spontaneous and N-ethyl-N-nitrosourea (ENU)-induced tumor models.
  • Investigation of RIPK3 deficiency in p53-null mice.
  • Assessment of extracellular signal-regulated kinase (ERK) signaling pathways.
  • Evaluation of lymphocyte-specific protein tyrosine kinase (LCK) and protein phosphatase 2 (PP2A) activity.

Main Results:

  • RIPK3 deficiency causes abnormal DP thymocyte proliferation, independent of necroptosis, leading to thymic masses.
  • Ripk3-null mice exhibit increased thymic tumor formation and reduced survival in an ENU-induced model.
  • RIPK3 deficiency in p53-null mice promotes thymic lymphoma via upregulated ERK signaling, decreasing survival.
  • LCK activates RIPK3, which enhances PP2A activity, suppressing ERK hyper-activation in DP thymocytes.

Conclusions:

  • A RIPK3-PP2A-ERK signaling axis regulates DP thymocyte homeostasis.
  • RIPK3 acts as a tumor suppressor in the thymus, controlling DP cell proliferation.
  • This pathway represents a potential therapeutic target for thymic lymphoma.
Keywords:
double-positive thymocytesextracellular signal-regulated kinase (ERK)lymphocyte-specific protein tyrosine kinase (LCK)protein phosphatase 2A (PP2A)receptor-interacting protein kinase 3 (RIPK3)thymic lymphoma

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