Abstract
Centrosomes control cell motility, polarity and migration that is thought to be mediated by their microtubule-organizing capacity. Here we demonstrate that WNT signalling drives a distinct form of non-directional cell motility that requires a key centrosome module, but not microtubules or centrosomes. Upon exosome mobilization of PCP-proteins, we show that DVL2 orchestrates recruitment of a CEP192-PLK4/AURKB complex to the cell cortex where PLK4/AURKB act redundantly to drive protrusive activity and cell motility. This is mediated by coordination of formin-dependent actin remodelling through displacement of cortically localized DAAM1 for DAAM2. Furthermore, abnormal expression of PLK4, AURKB and DAAM1 is associated with poor outcomes in breast and bladder cancers. Thus, a centrosomal module plays an atypical function in WNT signalling and actin nucleation that is critical for cancer cell motility and is associated with more aggressive cancers. These studies have broad implications in how contextual signalling controls distinct modes of cell migration.
Highlights
Centrosomes control cell motility, polarity and migration that is thought to be mediated by their microtubule-organizing capacity
We have previously shown that exosome-induced breast cancer cell (BCC) migration and invasive behaviour are regulated by the WNT signalling pathway which requires interplay with the planar cell polarity (PCP) pathway components[9]
We found that at the non-protrusive lateral membrane of protrusions, the PCP protein PK1 cooperates with the RhoGAPs Arhgap 21/23 to promote cell motility and protrusion formation
Summary
Centrosomes control cell motility, polarity and migration that is thought to be mediated by their microtubule-organizing capacity. Upon exosome mobilization of PCP-proteins, we show that DVL2 orchestrates recruitment of a CEP192-PLK4/AURKB complex to the cell cortex where PLK4/AURKB act redundantly to drive protrusive activity and cell motility This is mediated by coordination of formin-dependent actin remodelling through displacement of cortically localized DAAM1 for DAAM2. The formation of lamellipodia is predominantly mediated by the ARP2/3 complex, which induces actin meshworks in protrusions, and RAC, RHOA and CDC42 GTPases that are key regulators of cytoskeletal organisation[6] Filopodia, another important protrusive element can either emerge from lamellipodia or can form independently via formin-dependent regulation of actin polymerisation[7]. We previously demonstrated that exosomes secreted from activated fibroblasts and CAFs stimulate breast cancer cell (BCC) protrusive activity, motility, and metastasis through WNT-planar cell polarity (PCP) signalling[9]. FZD6, and asymmetric accumulation of FZD-DVL in protrusions, while VANGL and PRICKLE localise to the flanking lateral non-protrusive cortical regions[9], where they associate with
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