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Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1

Koko Katagiri1, Yoshihiro Ueda, Takashi Tomiyama

  • 1Department of Life Science, School of Science and Technology, Kwanseigakuen University, and JST, CREST, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan.

Immunity
|January 4, 2011
PubMed

Insights

RAPL protein regulates lymphocyte adhesion and proliferation. Its deficiency leads to autoimmune diseases and lymphoma by disrupting cell cycle control via p27(kip1) regulation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • RAPL (Ras-associated protein 1) is a known Rap1 effector regulating lymphocyte adhesion.
  • Its role in controlling lymphocyte proliferation and preventing lymphoproliferative disorders remains largely unexplored.

Purpose of the Study:

  • To investigate the novel function of RAPL in regulating lymphocyte proliferation and preventing autoimmunity and lymphoma.
  • To elucidate the molecular mechanism by which RAPL controls cell cycle progression.

Main Methods:

  • Utilized RAPL-deficient mouse models to study lymphocyte behavior and disease development.
  • Analyzed cell cycle progression, Cdk2 kinase activity, and p27(kip1) localization in lymphocytes.
  • Employed site-directed mutagenesis (S10A mutation) in p27(kip1) to assess its functional impact.

Main Results:

  • RAPL-deficient mice developed lupus-like glomerulonephritis and B cell lymphomas.
  • RAPL-deficient lymphocytes exhibited hyperproliferation due to enhanced S phase entry.
  • RAPL suppresses p27(kip1) phosphorylation at S10, promoting its nuclear translocation and inhibiting Cdk2 activity.

Conclusions:

  • RAPL acts as a critical checkpoint for S phase entry, preventing lymphoproliferative disorders.
  • The spatial regulation of p27(kip1) by RAPL is crucial for maintaining immune homeostasis.
  • Targeting the RAPL-p27(kip1) pathway may offer therapeutic strategies for autoimmune diseases and lymphoma.

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