Cancer can be considered a disease of abnormal cell division. We are investigating mechanisms by which abnormal tumour cell division may promotes oncogenesis.

Centrioles form the core of the centrosome, and in turn two centrosomes form the poles of the mitotic spindle, helping ensure faithful chromosome segregation. In epithelial cells, the mitotic spindle aligns with the plane of the epithelial layer, via interaction between astral microtubules and a lateral membrane complex containing NuMA, LGN and Dlg1. We have identified CASK as new component of the spindle orientation machinery, and showed that the interaction between CASK and Dlg1 is important for spindle orientation and lumen formation in 3D culture (Porter et al, JCS, 2019).

During the cell cycle, each centriole is licenced to produce a single daughter centriole, and in this way centriole number is tightly maintained. A major regulator of this process is the kinase PLK4. PLK4 activity drives centriole duplication, but this activity also leads to its own destruction through βTRCP-mediated degradation, ensuring once-per-cycle centriole duplication.

We have previously shown that the Rac1 GEF Tiam1 localises to centrosomes and is required for optimal centrosome separation during prophase to correctly form the mitotic spindle (Whalley et al, Nat Comms, 2015). Recently, we have uncovered a new role for Tiam1 in centriole duplication. Depletion of Tiam1 leads to centriole overduplication in U2OS and HCT116 cell lines. Depletion of Tiam1 also leads to lagging chromosomes at anaphase, a potential consequence of centriole overduplication. Depletion of Tiam1 leads to an increase in PLK4 staining at centrosomes. We are investigating a role for the N-terminus of Tiam1 which binds to βTRCP. Our hypothesis is that Tiam1 acts to ensure appropriate degradation of centrosomal PLK4. In support of this, Tiam1 protein which is unable to bind βTRCP is unable to rescue centriole overduplication resulting from Tiam1 depletion.