Mps1 etc.) are part of the check point, among which many have been identified to interact with Bub1. Upon activation of the SAC Bub1 directly phosphorylates APC/C’s coactivator Cdc20. This phosphorylation event is probably achieved in complex with Bub3, which itself has been subjected to prior phosphorylation by Bub1. The phosphorylation of Cdc20 ultimately leads to decreased activity of APC/C which determines the metaphase-to-anaphase transition. In turn APC/C, now in complex with Cdh1, also acts on Bub1 by priming it for degradation to exit mitosis. In addition, kinetochore localization of Bub1 early during G2 or prophase is another aspect of SAC functioning. Bub1 is thought to serve as a platform recruiting other checkpoint and motor proteins as Mad1, Mad2, BubR1, CENP-E and PLK1 to the kinetochore. Indeed, recent data suggest that the primary role of Bub1 during SAC activity is not Cdc20 phosphorylation but rather recruitment of BubR1, Mad1 and Mad2. Upon spindle damage Bub1 is also triggered to phosphorylate Mad1 leading to dissociation of the Mad1-Mad2 complex and thereby rendering Mad2 accessible for inhibition of Cdc20. Bub1 generally protects sister chromatide cohesion by enhancing Shugoshin protein (Sgo1) localization to the centromeric region. Through recruitment of the phosphatase PP2A Bub1 inhibits the action of PLK1, which removes Sgo1 from the centromere. Contrarily PLK1 localization, as mentioned, also depends on the activity of Bub1. Studies in Xenopus extracts using RNAi or antibody depletion have indicated a crucial function of Bub1 in the organization of the inner centromere. Similarly to its role in kinetochore assembly, it recruits members of the chromosomal passenger complex (CPC) like Aurora B kinase, Survivin and INCENP. Direct phosphorylation of INCENP by Bub1 has been observed. RNAi mediated depletion of human Bub1 has indicated function in correct metaphase congression. Downstream targets identified are distinct kinetochore proteins as CENP-F, MCAK and the mentioned Sgo1. Implications in cancer Disturbed mitotic checkpoints are a common feature of many human cancers. More precisely, mutations in the spindle checkpoint can lead to chromosomal instability and aneuploidy, a feature present in over 90% of all solid tumors. Loss-of-function mutations or reduced gene expression of Bub1 have been identified in several human tumors as colon, esophageal, gastric, breast cancer and melanoma. A correlation between Bub1 expression levels and the localization of tumors along with their severity was found. For instance, low Bub1 expression levels resulted in more sarcomas, lymphomas and lung tumors, whereas higher ones