Oncoprotein YAP Regulates the Spindle Checkpoint Activation in a Mitotic Phosphorylation-dependent Manner through Up-regulation of BubR1

Abstract

Background: Oncoprotein YAP regulates cell proliferation and tumorigenesis, and a cellular function of YAP in mitosis is largely unknown. Results: YAP and its mitotic phosphorylation regulate the spindle checkpoint through up-regulation of BubR1. Conclusion:The findings reveal a novel link between YAP and the spindle checkpoint. Significance: Our studies indicate a potential mechanism underlying the oncogenic function of YAP through dysregulation of the spindle checkpoint.

Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis

“…Interestingly, we also found that several Hippo core members (Lats1, Lats2, and Mst2) (Fig. 1) or their upstream regulator (KIBRA) (30,31) or downstream effectors (YAP and TAZ) (12,13,15) are phosphorylated during mitosis. Importantly, mitotic phosphorylation is critical for their oncogenic or tumor suppressive functions (12,13,15).…”

“…For example, loss of core tumor suppressors in the Hippo pathway (including Lats2, Mst1/2, Mob1, and WW45) leads to severe defects in multiple mitotic processes (39 -41). Accordingly, we recently reported that overexpression of active YAP (12,13) or TAZ (15) is sufficient to trigger mitotic defects, including centrosome amplification, spindle disorganization, chromosome misalignment, and subsequent aneuploidy. Interestingly, we also found that several Hippo core members (Lats1, Lats2, and Mst2) (Fig.…”

“…We have shown that KIBRA (an upstream regulator of the Hippo pathway) (30,31), YAP (12, 13), and TAZ (15) are phosphorylated by mitotic kinases. Importantly, mitotic phosphorylation of YAP/ TAZ is critical for proper mitotic progression and for their oncogenic activity in cancer cells (12,13,15). These studies prompted us to further examine whether other components or regulators of the Hippo pathway are regulated by phosphorylation during mitosis.…”

“…This core kinase signaling subsequently phosphorylates and inactivates the downstream effectors, oncoproteins YAP and TAZ, by sequestering them in the cytoplasm and promoting ubiquitination-dependent degradation (5). During past years, many regulators and input signals have been identified that influence Hippo-YAP signaling activity, such as the cell polarity and adherens junctions proteins, mechanical force, actin cytoskeleton (6 -8), hypoxia (9), energy stress (10,11), and mitosis/cytokinesis stress (12)(13)(14)(15). The downstream effectors YAP/TAZ also cross-talk with, or function as, mediators of many other signaling pathways, such as the G-protein coupled receptor, Wnt/␤-catenin, TGF-␤/SMAD, EGF, Notch, Hedgehog, and KRas/MAPK pathways (16).…”

Mechanisms of Hippo pathway regulation

“…YAP and TAZ are phosphorylated at multiple sites by CDK1 during the G2/M phase of the cell cycle (Yang et al 2013(Yang et al , 2015bZhao et al 2014;Dent et al 2015;Zhao and Yang 2015). However, the physiological outcomes of these phosphorylation events are rather perplexing, as their effects on cell growth and migration are not entirely consistent among reports from different groups.…”