CETN3 regulates centrosome duplication by antagonizing the kinase activity of Mps1 (Monopolar spindle 1), a critical regulator of centriole assembly . Key mechanistic insights:
Mps1 Inhibition: CETN3 binds Mps1 and blocks its autophosphorylation at Thr676, reducing Mps1's ability to phosphorylate substrates like CETN2 .
Centriole Assembly: Overexpression of CETN3 in HeLa cells reduces centrosome reduplication by 50%, while CETN3 depletion increases Mps1 activity and promotes aberrant centriole formation .
Functional Distinction: Unlike CETN2, CETN3 does not support DNA damage response but specifically modulates centrosomal Mps1 activity .
CETN3 exhibits 4,930 functional associations across biological categories, including interactions with cell cycle regulators and structural proteins . Tissue expression analysis reveals:
Tissue Group | Expression Level | Notable Tissues |
---|---|---|
Reproductive Organs | High | Testis, ovary, prostate |
Neural Tissues | Moderate | Cerebral cortex, hippocampus |
Gastrointestinal Tract | Low | Colon, small intestine |
Data sourced from transcriptomic studies show widespread but variable expression, with elevated levels in proliferating cells .
Centrin-3 contains four EF-hand calcium-binding domains, which are characteristic of the centrin protein family . These domains enable the protein to bind calcium ions, which is crucial for its function. Centrins, including Centrin-3, are primarily associated with the centrosome, a key organelle involved in the organization of microtubules and the regulation of the cell cycle .
Centrin-3 plays a significant role in centrosome reproduction, which is essential for the bipolarity of cell division . The centrosome must duplicate once per cell cycle to ensure proper cell division. Studies have shown that the localization of Centrin-3 to the centriole depends on a functional fourth EF-hand . Overexpression of wild-type or mutant forms of Centrin-3 in human cells has demonstrated that while centriole localization is affected, it does not produce a mitotic phenotype .
The centrin family of proteins, including Centrin-3, is highly conserved across different species. This conservation suggests that the fundamental mechanisms of centrosome duplication and function are preserved throughout evolution . In yeast, the CDC31 protein is located at the centrosome of interphase and mitotic cells, where it plays a crucial role in centrosome duplication and separation . Similarly, Centrin-3 in humans is one of the most abundant centrins associated with the centrosome, indicating a similar function to its yeast counterpart .
Research on Centrin-3 has provided valuable insights into the molecular mechanisms underlying centrosome duplication and cell division. The study of recombinant forms of Centrin-3, such as human recombinant Centrin-3, has allowed scientists to investigate its specific functions and interactions within the cell. These studies have implications for understanding various cellular processes and potential applications in medical research and biotechnology.