Atypical function of a centrosomal module in WNT signalling drives contextual cancer cell motility

Yi Luo; Miriam Barrios-Rodiles; Gagan D Gupta; Ying Y Zhang; Abiodun A Ogunjimi; Mikhail Bashkurov; Johnny M Tkach; Ainsley Q Underhill; Liang Zhang; Mohamed Bourmoum; Jeffrey L Wrana; Laurence Pelletier

doi:10.1038/s41467-019-10241-w

Atypical function of a centrosomal module in WNT signalling drives contextual cancer cell motility

Nat Commun. 2019 May 29;10(1):2356. doi: 10.1038/s41467-019-10241-w.

Authors

Yi Luo¹, Miriam Barrios-Rodiles¹, Gagan D Gupta^{1

2}, Ying Y Zhang^{1

3}, Abiodun A Ogunjimi¹, Mikhail Bashkurov¹, Johnny M Tkach¹, Ainsley Q Underhill^{1

3}, Liang Zhang^{1

4}, Mohamed Bourmoum¹, Jeffrey L Wrana^{1

3}, Laurence Pelletier^{5

6}

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
² Department of Chemistry and Biology, Ryerson University, Toronto, ON, M5B 2K3, Canada.
³ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁴ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
⁵ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. [email protected].
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Adaptor Proteins, Signal Transducing / metabolism
Aurora Kinase B / metabolism*
Breast Neoplasms / metabolism
Carcinoma, Transitional Cell / metabolism
Cell Line, Tumor
Cell Movement*
Centrosome / metabolism*
Chromosomal Proteins, Non-Histone / metabolism*
Dishevelled Proteins / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Microfilament Proteins / metabolism
Neoplasms / metabolism*
Prognosis
Protein Interaction Maps
Protein Serine-Threonine Kinases / metabolism*
Real-Time Polymerase Chain Reaction
Urinary Bladder Neoplasms / metabolism
Wnt Signaling Pathway*
rho GTP-Binding Proteins

Substances

Actins
Adaptor Proteins, Signal Transducing
Cep192 protein, human
Chromosomal Proteins, Non-Histone
DAAM1 protein, human
DAAM2 protein, human
DVL2 protein, human
Dishevelled Proteins
Intracellular Signaling Peptides and Proteins
Microfilament Proteins
PLK4 protein, human
AURKB protein, human
Aurora Kinase B
Protein Serine-Threonine Kinases
rho GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding