mitotic checkpoint serine/threonine protein kinase BUB1; hBUB1; BUB1A (BUB1, BUB1L)
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Function
- serine/threonine protein kinase
- performs 2 crucial functions during mitosis
- essential for spindle-assembly checkpoint signaling
- correct chromosome alignment
- role in assembly of checkpoint proteins at the kinetochore
- role in SGOL1 localization & thus affects sister chromatid cohesion
- substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1)
- necessary for ensuring proper chromosome segregation as component of BUB1/BUB3 complex
- can regulate chromosome segregation (kinetochore-independent)
- can phosphorylate BUB3
- component of BUB1/BUB3 complex
- mediates cell death in response to chromosome missegregation & acts to suppress spontaneous tumorigenesis
- autophosphorylated when the cells enters mitosis
- phosphorylated upon DNA damage, probably by ATM or ATR
- upon spindle-assembly checkpoint activation, it is hyperphosphorylated & its kinase activity toward CDC20 is stimulated
- phosphorylation at Thr-609 is required for interaction with PLK1; phosphorylation probably creates a binding site for the POLO-box domain of PLK1, thus enhancing the PLK1-BUB1 interaction
- ubiquitinated & degraded during mitotic exit by APC/C-Cdh1
- interacts with BUB3 & CASC5
- interacts (when phosphorylated) with PLK1
Structure
- CD1 domain directs kinetochore localization & binding to BUB3
- the KEN box is required for its ubiquitination & degradation
- belongs to the protein kinase superfamily, Ser/Thr protein kinase family, BUB1 subfamily
- contains 1 CD1 domain
- contains 1 protein kinase domain
Compartment
- nucleus
- kinetochore
- nuclear in interphase cells
- accumulates gradually during G1 & S phase of the cell cycle, peaks at G2/M, & drops dramatically after mitosis
- localizes to the outer kinetochore
- kinetochore localization is required for normal mitotic timing & checkpoint response to spindle damage & occurs very early in prophase
- AURKB, CASC5 & INCENP are required for kinetochore localization
Expression
- high expression in testis & thymus
- less in colon, spleen, lung & small intestine
- expressed in fetal thymus, bone marrow, heart, liver, spleen & thymus
- expression is associated with cells/tissues with a high mitotic index
- inhibited by phorbol 12-myristate 13-acetate (PMA)