Tumour suppressor CYLD is a negative regulator of the mitotic kinase Aurora-B.
The familial cylindromatosis tumour suppressor CYLD contains three cytoskeleton-associated protein glycine-rich (CAP-Gly) domains and a deubiquitinase domain. The tumour-suppressing function of CYLD has been attributed to its deubiquitinase domain, which removes lysine-63-linked polyubiquitin chains from target proteins, leading to the inhibition of cell survival and proliferation. In this study, we have detected an interaction of CYLD with the mitotic kinase Aurora-B. The interaction is mediated by the third CAP-Gly domain of CYLD and results in suppression of Aurora-B activity. Mechanistic studies reveal that the inhibition of Aurora-B activity by CYLD is independent of its deubiquitinase activity. Instead, CYLD interacts with protein phosphatase 2A (PP2A) and promotes the ability of PP2A to bind and dephosphorylate Aurora-B at threonine-232. Cylindromatosis-associated truncating mutations of CYLD abolish its interaction with PP2A, its enhancing effect on the PP2A/Aurora-B interaction, and its inhibitory effect on Aurora-B activity. These findings uncover Aurora-B and PP2A as novel binding partners of CYLD and suggest that CYLD negatively regulates Aurora-B activity through acting on the PP2A axis.
Sun
Lei
L
Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China.
Gao
Jinmin
J
Huo
Lihong
L
Sun
Xiaoou
X
Shi
Xingjuan
X
Liu
Min
M
Li
Dengwen
D
Zhang
Chuanmao
C
Zhou
Jun
J
D064107:Aurora Kinase B; D064127:Aurora Kinases; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D025521:Tumor Suppressor Proteins; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD