Mitotic spindle regulation by novel Aurora A control mechanisms [The Robert Baillie Research Grant] (2016-2018)
Abstract
Mitotic signalling regulation of the cytoskeleton by Aurora A kinase (AURKA) determines spindle architecture, division orientation and specification of daughter cells through inheritance of fate determinants. Defects in AURKA signalling trigger genetic instability, segregation errors and altered proliferation/differentiation to cause growth abnormalities, tissue disorganization and increased tumourgenesis. Thus, elucidation of spindle-associated AURKA mechanisms would provide great utility in the diagnosis, treatment and aetiology of intractable human diseases. This proposal builds on our recent finding that AURKA regulates metaphase spindle stability in a complex with c-Jun N-terminal kinases (JNK) and its associated scaffold, WD-Repeat Protein 62 (WDR62). Excitingly, our discovery has the potential to inform on the AURKA regulatory network active during metaphase progression, a critical juncture in mitosis, where we hypothesize that the AURKA/WDR62/JNK complex controls high fidelity segregation of cellular components, division orientation and mitotic timing that is crucial for tissue growth. We will capitalize on our combined expertise in cell cycle regulation, signal transduction, drosophila genetics and mouse models to reveal the molecular and biochemical basis of AURKA/WDR62/JNK control of neural proliferation and differentiation. Our aims in this context are to: Aim 1: Define targets of AURKA/WDR62/JNK signalling involved in spindle control. Aim 2: Dissect metaphase assembly of the AURKA/WDR62 signalling complex. Aim 3: Determine the role of AURKA/WDR62/JNK in normal and pathological tissue growth. Research outcomes will increase mechanistic understanding of progenitor cell divisions that underpin tissue growth in multiple biological systems to potentially impact a broad range of human diseases and thus is highly relevant to human health.
