By phosphorylating Thr3 of histone H3, Haspin promotes centromeric recruitment of the chromosome passenger complex (CPC) during mitosis. Aurora B kinase, a CPC subunit, sustains chromosome bi-orientation and the spindle assembly checkpoint (SAC). Here, we characterize the small molecule 5-iodotubercidin (5-ITu) as a potent Haspin inhibitor. In vitro, 5-ITu potently inhibited Haspin but not Aurora B. Consistently, 5-ITu counteracted the centromeric localization of the CPC without affecting the bulk of Aurora B activity in HeLa cells. Mislocalization of Aurora B correlated with dephosphorylation of CENP-A and Hec1 and SAC override at high nocodazole concentrations. 5-ITu also impaired kinetochore recruitment of Bub1 and BubR1 kinases, and this effect was reversed by concomitant inhibition of phosphatase activity. Forcing localization of Aurora B to centromeres in 5-ITu also restored Bub1 and BubR1 localization but failed to rescue the SAC override. This result suggests that a target of 5-ITu, possibly Haspin itself, may further contribute to SAC signaling downstream of Aurora B.
A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B / A. De Antoni, S. Maffini, S. Knapp, A. Musacchio, S. Santaguida. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 199:2(2012), pp. 269-284.
|Titolo:||A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B|
SANTAGUIDA, STEFANO (Corresponding)
|Parole Chiave:||Chromosomal passenger complex; spindle-assembly checkpoint; protein phosphatase 1; histone h3 phosphorylation; MPS1 kinase-activity; microtubule attachment; mitotic checkpoint; cell-division; THR-3 phosporylation; adenosine kinase|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1083/jcb.201205119|
|Appare nelle tipologie:||01 - Articolo su periodico|