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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function.

Anil Kumar Ganga1, Lauren K Sweeney1, Armando Rubio Ramos2

  • 1Department of Molecular, Cellular and Developmental Biology, Yale University, 260 Whitney Avenue, New Haven, CT 06511, USA.

Current Biology : CB
|September 24, 2024
PubMed
Summary

Centrosome regulation is key to cell function and disease. This study identifies PPP2R3C as a distal centriole protein that counteracts MAP3K1 kinase activity, revealing a new phospho-regulatory module linked to gonadal development disorders.

Keywords:
DepMapPP2Acentriolecentrosomeciliafunctional genomicsgonadal dysgenesiskinaseneuroblastomaphosphatase

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Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • Centrosomes are crucial for microtubule organization, ciliogenesis, and cell signaling, with alterations linked to diseases like cancer and ciliopathies.
  • Over 150 centrosomal proteins are known, including kinases and phosphatases, but regulatory mechanisms and disease links remain incompletely understood.
  • Systems genetics approaches can uncover novel gene functions and regulatory pathways in cellular processes.

Purpose of the Study:

  • To investigate the function of the poorly characterized PP2A phosphatase subunit, PPP2R3C, within the centrosome.
  • To elucidate the regulatory interactions between PPP2R3C and other centrosomal proteins, particularly kinases.
  • To understand the role of the PPP2R3C-MAP3K1 axis in centrosome function and its implications in human diseases.

Main Methods:

  • Systems genetics approach to identify functional centrosomal proteins.
  • Biochemical assays to determine protein interactions and enzymatic activities (e.g., kinase and phosphatase activity).
  • Genetic manipulation (knockout and overexpression) to assess functional consequences of PPP2R3C and MAP3K1.
  • Analysis of patient-derived mutations to link molecular findings to clinical phenotypes.

Main Results:

  • PPP2R3C is identified as a distal centriole protein and a functional partner of CEP350 and FOP.
  • PPP2R3C counteracts the kinase activity of MAP3K1, impacting JNK signaling pathways.
  • MAP3K1 knockout rescues growth defects from PPP2R3C inactivation; MAP3K1 overexpression causes centriole disintegration.
  • Mutations in PPP2R3C and MAP3K1 are associated with congenital syndromes involving gonadal dysgenesis, with syndromic PPP2R3C variants showing impaired centriolar localization.

Conclusions:

  • A novel centrosomal phospho-regulatory module involving PPP2R3C and MAP3K1 is revealed.
  • Imbalanced activity of this kinase-phosphatase pair is proposed as the cause of gonadal development disorders.
  • Systems genetics effectively identifies new gene functions and provides insights into disease mechanisms.