Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Abstract

Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.

Myb-binding Protein 1a (Mybbp1a) Regulates Levels and Processing of Pre-ribosomal RNA

“…In agreement with previous observations (44,45), Mybbp1a preferentially localizes to the nucleolus also in HeLa cells as shown by immunofluorescence experiments that detect the endogenous human protein and transiently transfected mouse and human FLAG-Mybbp1a protein (Fig. 1E).…”

“…Both Rrs1 and Ebp2 have recently been connected to a role in the progression of mitosis as well. Mybbp1a is phosphorylated by the mitotic kinase Aurora B, and it has been revealed that depletion of Mybbp1a or Rrs1 leads to a mitotic delay and abnormalities in spindle organization (45,68). Additionally, the involvement of Mybbp1a, rpL5, and rpL11 was shown in p53 acetylation and accumulation, which is dependent on the release of Mybbp1a from nucleolar RNA upon stress (54).…”

TPPII, MYBBP1A and CDK2 form a protein–protein interaction network

“…All the interacting proteins described here were previously implicated in the research for development of tumor suppressing agents. MYBBP1A has multiple functions in cancer cells via its p53 activation effect [1], by being a substrate of Aurora kinase B considered as drug target for cancer therapy [18] and by its function as a corepressor of the transcription factor NFjB [17]. TPPII inhibitors have been suggested as potential tumor-suppressing agents [4], and some inhibitors of CDK-s with effect on cell cycle arrest at G1/S checkpoint have cytostatic effects [16].…”

Zebrafish midbrain slow-amplifying progenitors exhibit high levels of transcripts for nucleotide and ribosome biogenesis

“…The gene mybbp1a is located at a key node of the established PML network. This gene has been shown to activate p53 when ribosome biogenesis is suppressed (Tsuchiya et al, 2011) and Mybbp1a might be part of a nucleolar pool of proteins involved in mitotic progression (Perrera et al, 2010). Further studies are needed to clarify the role of Mybbp1a in NSCs and SAPs by focusing on the interplay between its nucleolar and cell cycle-associated functions.…”