Abstract
ABSTRACTTimely activation of Aurora kinase A (AURA, also known as AURKA) is vital for centrosome formation and the progression of mitosis. Nonetheless, it is still unclear if and when other cellular functions are activated by AURA. We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement. An additional and new way by which AURA is regulated, is by phospholipase D2 (PLD2), which causes AURA activation. In addition, AURA phosphorylates PLD, so both proteins engage in a positive reinforcement loop. AURA and PLD2 form a protein–protein complex and colocalize to cytoplasmic regions in cells. The reason why PLD activates AURA is because of the production of phosphatidic acid by the lipase, which binds directly to AURA, with the region E171–E211 projected to be a phosphatidic-acid-binding pocket. Furthermore, this direct interaction with phosphatidic acid enhances tubulin polymerization and cooperates synergistically with AURA, FAK and Src in yielding a fully effectual cellular migration. Thus, Src and FAK, and PLD and phosphatidic acid are new upstream regulators of AURA that mediate its role in the non-mitotic cellular function of cell migration.
Highlights
Mitosis is mediated by phosphorylation and dephosphorylation of specific substrates by many different protein kinases, such as the Polo-like kinases (PLKs), the cyclin-dependent kinases (CDKs), the never in mitosis gene a kinase (NIMA) and the aurora kinases (AURKs)
AURA is essential for enhanced cell migration In Fig. 1A, enhanced cell migration of COS-7 fibroblasts towards 3 nM EGF was mediated by endogenous AURA, as the presence of the AURA-specific small-molecule inhibitor, AM-8237 (30 nM) significantly reduced migration
Silencing AURA reduces cell migration by modulating tubulin Having shown that overexpression of AURA enhanced cell migration, we wanted to determine the effect of silencing AURA on enhanced cell migration
Summary
Mitosis is mediated by phosphorylation and dephosphorylation of specific substrates by many different protein kinases, such as the Polo-like kinases (PLKs), the cyclin-dependent kinases (CDKs), the never in mitosis gene a kinase (NIMA) and the aurora kinases (AURKs). The Aurora kinase A isoform (AURA, known as AURKA and STK15), is a 403-amino-acid 46 kDa protein that promotes microtubule nucleation around the chromatin, through phosphorylation of NEDD1, and functional spindle assembly in mitotic cells (Yang et al, 2000; Pinyol et al, 2013). AURA is localized to centrosomes during G2 and mitosis on the mitotic spindle (Vader and Lens, 2008). AURA is associated with microtubules in the cytoplasm (Vader and Lens, 2008)
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