Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ipl1/Aurora B is the catalytic subunit of a protein kinase complex required for chromosome segregation and nuclear division. Before anaphase, Ipl1 is required to establish proper kinetochore-microtubule associations and to regulate the spindle assembly checkpoint (SAC). The phosphatase Glc7/PP1 opposes Ipl1 for these activities. To investigate Ipl1 and Glc7 regulation in more detail, we isolated and characterized mutations in the yeast Saccharomyces cerevisiae that raise the restrictive temperature of the ipl-2 mutant. These suppressors include three intragenic, second-site revertants in IPL1; 17 mutations in Glc7 phosphatase components (GLC7, SDS22, YPI1); two mutations in SHP1, encoding a regulator of the AAA ATPase Cdc48; and a mutation in TCO89, encoding a subunit of the TOR Complex 1. Two revertants contain missense mutations in microtubule binding components of the kinetochore. rev76 contains the missense mutation duo1-S115F, which alters an essential component of the DAM1/DASH complex. The mutant is cold sensitive and arrests in G2/M due to activation of the SAC. rev8 contains the missense mutation ndc80-K204E. K204 of Ndc80 corresponds to K166 of human Ndc80 and the human Ndc80 K166E variant was previously shown to be defective for microtubule binding in vitro. In a wild-type IPL1 background, ndc80-K204E cells grow slowly and the SAC is activated. The slow growth and cell cycle delay of ndc80-K204E cells are partially alleviated by the ipl1-2 mutation. These data provide biological confirmation of a biochemically based model for the effect of phosphorylation on Ndc80 function.
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PMID:Suppressors of ipl1-2 in components of a Glc7 phosphatase complex, Cdc48 AAA ATPase, TORC1, and the kinetochore. 2327 90

The conserved, ubiquitin-selective AAA ATPase Cdc48 regulates numerous cellular processes including protein quality control, DNA repair and the cell cycle. Cdc48 function is tightly controlled by a multitude of cofactors mediating substrate specificity and processing. The UBX domain protein Shp1 is a bona fide substrate-recruiting cofactor of Cdc48 in the budding yeast S. cerevisiae. Even though Shp1 has been proposed to be a positive regulator of Glc7, the catalytic subunit of protein phosphatase 1 in S. cerevisiae, its cellular functions in complex with Cdc48 remain largely unknown. Here we show that deletion of the SHP1 gene results in severe growth defects and a cell cycle delay at the metaphase to anaphase transition caused by reduced Glc7 activity. Using an engineered Cdc48 binding-deficient variant of Shp1, we establish the Cdc48(Shp1) complex as a critical regulator of mitotic Glc7 activity. We demonstrate that shp1 mutants possess a perturbed balance of Glc7 phosphatase and Ipl1 (Aurora B) kinase activities and show that hyper-phosphorylation of the kinetochore protein Dam1, a key mitotic substrate of Glc7 and Ipl1, is a critical defect in shp1. We also show for the first time a physical interaction between Glc7 and Shp1 in vivo. Whereas loss of Shp1 does not significantly affect Glc7 protein levels or localization, it causes reduced binding of the activator protein Glc8 to Glc7. Our data suggest that the Cdc48(Shp1) complex controls Glc7 activity by regulating its interaction with Glc8 and possibly further regulatory subunits.
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PMID:The budding yeast Cdc48(Shp1) complex promotes cell cycle progression by positive regulation of protein phosphatase 1 (Glc7). 2341 75

Protein phosphatase 1 (PP1) controls many aspects of cell physiology, which depends on its correct targeting in the cell. Nuclear localization of Glc7, the catalytic subunit of PP1 in budding yeast, requires the AAA-ATPase Cdc48 and its adaptor Shp1 through an unknown mechanism. Herein, we show that mutations in SHP1 cause misfolding of Glc7 that co-aggregates with Hsp104 and Hsp42 chaperones and requires the proteasome for clearance. Mutation or depletion of the PP1 regulatory subunits Sds22 and Ypi1, which are involved in nuclear targeting of Glc7, also produce Glc7 aggregates, indicating that association with regulatory subunits stabilizes Glc7 conformation. Use of a substrate-trap Cdc48(QQ) mutant reveals that Glc7-Sds22-Ypi1 transiently associates with and is the major target of Cdc48-Shp1. Furthermore, Cdc48-Shp1 binds and prevents misfolding of PP1-like phosphatases Ppz2 and Ppq1, but not other types of phosphatases. Our data suggest that Cdc48-Shp1 functions as a molecular chaperone for the structural integrity of PP1 complex in general and that it specifically promotes the assembly of Glc7-Sds22-Ypi1 for nuclear import.
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PMID:Assembly and quality control of the protein phosphatase 1 holoenzyme involves the Cdc48-Shp1 chaperone. 2561 96