Journal
JOURNAL OF CELL SCIENCE
Volume 134, Issue 7, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.252502
Keywords
Centriole; Centriole duplication; PLK4; Tiam1; beta TRCP; Aneuploidy
Categories
Funding
- Cancer Research UK [C5759/A20410]
- Worldwide Cancer Research [16-0379]
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Tiam1 plays a crucial role in regulating centriole duplication by maintaining normal centriole number and preventing overduplication, ultimately affecting chromosome segregation and potentially driving malignant progression. Tiam1 regulates PLK4 levels through promoting beta TRCP-mediated degradation independently of Rac1 activation.
Centriole duplication is tightly controlled to maintain correct centriole number through the cell cycle. Key to this is the regulated degradation of PLK4, the master regulator of centriole duplication. Here, we show that the Rac1 guanine nucleotide exchange factor (GEF) Tiam1 localises to centrosomes during S-phase, where it is required for the maintenance of normal centriole number. Depletion of Tiam1 leads to an increase in centrosomal PLK4 and centriole overduplication, whereas overexpression of Tiam1 can restrict centriole overduplication. Ultimately, Tiam1 depletion leads to lagging chromosomes at anaphase and aneuploidy, which are potential drivers of malignant progression. The effects of Tiam1 depletion on centrosomal PLK4 levels and centriole overduplication can be rescued by re-expression of both wild-type Tiam1 and catalytically inactive (GEF*) Tiam1, but not by Tiam1 mutants unable to bind to the F box protein beta TRCP (also known as F-boxNVD repeat containing protein 1A) implying that Tiam1 regulates PLK4 levels through promoting beta TRCP-mediated degradation independently of Rac1 activation.
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