The RAC1 activator Tiam1 regulates centriole duplication through controlling PLK4 levels

Abstract

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 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, 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 βTRCP, implying that Tiam1 regulates PLK4 levels through promoting βTRCP-mediated degradation independently of Rac1 activation.

A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells

“…3 C ), suggesting that nuclear TIAM1 requires RAC1 activity to promote NSCLC cell migration. Importantly, using a previously described “GEF-dead” TIAM1 mutant (GD-TIAM1) ( 20 , 37 , 39 , 40 ), we were able to assess whether the GEF activity of TIAM1 was required to promote migration. Both NLS- and NLS-GD-TIAM1 proteins were localized to the nucleus following addition of doxycycline ( SI Appendix , Fig.…”

The Dual Function of RhoGDI2 in Immunity and Cancer

“…Besides transport, mobility and mechanical support, the microtubule cytoskeleton is also involved in chromosome segregation, centriole duplication and formation of primary cilia [ 98 , 99 , 100 ]. Rho GTPases have been extensively probed for their roles in processes involved in centriole duplication and cell division [ 101 , 102 , 103 ]. Despite the extensive research done to scrutinize RhoGDI2 for its involvement in multiple human cancers, no work has been done to investigate if and how RhoGDI2 is involved in the different steps regulating cell division.…”