Phosphoserine Dependant Assembly of Signaling complexes

信号复合物的磷酸丝氨酸依赖性组装

• 批准号: 7283024
• 负责人: MICHAEL B YAFFE
• 金额: $ 28.22万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283024
• 关键词: 14-3-3 Proteins; Antineoplastic Agents; BRCT Domain; Binding; Biochemical; Biological; C-terminal; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Proliferation Regulation; Cells; Centrosome; Complex; DNA Damage; Development; Disease regression; Down-Regulation; Drug Design; Eukaryotic Cell; Event; F-Box Proteins; FHA Domain; Funding; Genotoxic Stress; Goals; Human; Laboratories; Ligand Binding; Ligands; Malignant - descriptor; Malignant Neoplasms; Mitosis; Mitotic; Mitotic spindle; Molecular; N-terminal; Normal Cell; Numbers; Pharmaceutical Preparations; Phosphopeptides; Phosphorylation; Phosphoserine; Phosphothreonine; Phosphotransferases; Physiological; Play; Polo-Box Domain; Process; Protein Kinase; Protein Overexpression; Proteins; Proteomics; Recruitment Activity; Regulation; Role; Screening procedure; Signal Transduction; Signaling Protein; Staging; Techniques; Tertiary Protein Structure; Threonine; Time; WD Repeat; Work; base; human PLK1 protein; neoplastic; novel; research study; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Phosphoserine/threonine-binding domains play critical roles in controlling multiple aspects of cell proliferation, including cell cycle progression and the cellular response to DNA damage. The current list of pSer/pThr-binding domains includes 14-3-3 proteins, FHA domains, WW domains, WD40 repeats of F-box proteins, tandem BRCT domains and the Polo-box domains of Polo-like kinases. The long-term goal of our laboratory is to identify and characterize these domains with a focus on identifying their physiological ligands, determining the structural basis for their pSer/Thr-motif recognition, and elucidating the molecular basis for their functions in cell cycle control within complex protein kinase signaling networks. Polo-like kinases are essential during multiple stages of the eukaryotic cell cycle, including many of the events that occur during M-phase, as well as in the DNA damage response. Despite their importance, details about how Polo-like kinase activity is regulated, and the identity of their substrates are poorly understood. In this proposal we use a combination of biochemical, structural and cell biological techniques to determine the function of the invariant pSer/pThr-binding Polo-box domain in regulating the activation of, and the substrate selection and phosphorylation by Polo-like kinases. In the process, we will identify many new Polo-like kinase ligands and substrates that may be responsible for the pleiotropic role these kinases play in the cell. Since Polo-like kinases are upregulated in many types of human cancer, and since their experimental down-regulation results in decreased cell proliferation and tumor regression, the results of our experiments should determine whether the Polo-box domain is a good target for novel anti-cancer drug design.

描述（由申请人提供）：

项目成果

Cytokine-induced signaling networks prioritize dynamic range over signal strength.

• DOI: 10.1016/j.cell.2008.08.034
• 发表时间: 2008-10-17
• 期刊: Cell
• 影响因子: 64.5
• 作者: Janes KA;Reinhardt HC;Yaffe MB
• 通讯作者: Yaffe MB

Linear motif atlas for phosphorylation-dependent signaling.

• DOI: 10.1126/scisignal.1159433
• 发表时间: 2008-09-02
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Miller ML;Jensen LJ;Diella F;Jørgensen C;Tinti M;Li L;Hsiung M;Parker SA;Bordeaux J;Sicheritz-Ponten T;Olhovsky M;Pasculescu A;Alexander J;Knapp S;Blom N;Bork P;Li S;Cesareni G;Pawson T;Turk BE;Yaffe MB;Brunak S;Linding R
• 通讯作者: Linding R

Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2.

• DOI: 10.1016/j.ceb.2009.01.018
• 发表时间: 2009-04
• 期刊: Current opinion in cell biology
• 影响因子: 7.5
• 作者: Reinhardt HC;Yaffe MB
• 通讯作者: Yaffe MB

Peptoid-Peptide hybrid ligands targeting the polo box domain of polo-like kinase 1.

• DOI: 10.1002/cbic.201200206
• 发表时间: 2012-06-18
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Liu F;Park JE;Qian WJ;Lim D;Scharow A;Berg T;Yaffe MB;Lee KS;Burke TR Jr
• 通讯作者: Burke TR Jr

NetworKIN: a resource for exploring cellular phosphorylation networks.

• DOI: 10.1093/nar/gkm902
• 发表时间: 2008-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Linding R;Jensen LJ;Pasculescu A;Olhovsky M;Colwill K;Bork P;Yaffe MB;Pawson T
• 通讯作者: Pawson T