FBXL 13 directs the proteolysis of CEP 192 to regulate centrosome homeostasis and cell migration

Abstract

Aberrant centrosome organisation with ensuing alterations of microtubule nucleation capacity enables tumour cells to proliferate and invade despite increased genomic instability. CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here, we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152 and CEP192. Among these, CEP192 is specifically targeted for proteasomal degradation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal γ-tubulin and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and γ-tubulin at the centrosomes with the consequence of defects in cell motility. Together, we characterise FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumour-promoting implications.

Effects of SAHA and EGCG on Growth Potentiation of Triple-Negative Breast Cancer Cells

“…There appeared to be a decrease in migration in the MDA-MB-231 cell line compared to the control, but this was not significant (Figure 10C). The area of the scratch was measured using the MRI Wound Healing Tool macro designed for ImageJ, as cited in recent papers [20,21]. Because of the general decrease in cellular migration, E-cadherin and N-cadherin levels were quantified (Figure 11).…”

The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer

“…Numerous lines of evidence demonstrate that SCF complex components promote the ubiquitination and degradation of regulatory proteins and play roles in tumorigenesis and progression 4 , 81 . The function of Skp1 is very important in cellular activities, including the ubiquitination of cell-cycle-related proteins 82 , kinetochore function, cell division 83 , 84 , and tumor formation 85 .…”

Differential turnover of Nup188 controls its levels at centrosomes and role in centriole duplication

“…The expectation is that Nup188’s turnover is inhibited during G2 and early M-phase to elevate its levels and then stimulated at the end of mitosis to trigger its degradation. While we have not yet identified the molecular players that control this behavior, clear candidates are E3 ubiquitin ligases such as the anaphase-promoting complex or the SKP-CUL1-F Box complex, which have both been implicated in centrosome function by impacting the degradation of PCM components (Arquint et al, 2018; Cunha-Ferreira et al, 2009; D’Angiolella et al, 2010; Drosopoulos et al, 2014; Freed et al, 1999; Fung et al, 2018; Holland et al, 2010; Piva et al, 2002; Prosser et al, 2012). Other E3 ligases have also been implicated as functioning at centrosomes including Mib1 (Čajánek et al, 2015).…”