| title: | Protein kinase signaling networks in the eukaryotic cell cycle |
|---|---|
| reg no: | ETF6766 |
| project type: | Estonian Science Foundation research grant |
| subject: |
1.7. Organic Chemistry and Biochemistry |
| status: | accepted |
| institution: | Tartu University Institute of Technology |
| head of project: | Mart Loog |
| duration: | 01.01.2006 - 31.12.2009 |
| description: | Protein kinases are critical regulatory molecules governing numerous cellular processes, and defects in kinase signaling are associated with many diseases, including cancer. I focus on understanding how kinase signaling networks are organized, with an emphasis on the mechanisms that determine substrate specificity. Recently, we showed that substrate targeting specificity of protein kinase Cdk1, the master regulator of cell cycle, is differentially modulated by different cyclins. Subsequently, I found that different cyclins gradually change both Cdk1 kinetic properties and the specificity of G2/M inhibitory kinase Swe1 towards Cdk1. This striking finding suggests that Swe1 acts as a “Km sensor”, sensing which cyclin is bound to Cdk1. This enables efficient separation of S-phase and M-phase signals and ensures that DNA replication precedes mitosis. In the first part of the project, I will apply several strategies to study the molecular basis of this entirely novel concept of cell cycle regulation. For the second part of the project, I propose to study the mechanism and function of multisite phosphorylation by cell cycle kinases. Most kinases phosphorylate multiple sites on their targets, but the reason for such signal processing is poorly understood. We will evaluate the benefits of distributive vs processive phosphorylation and the influence of multi-site clusters on phosphorylation signal ultrasensitivity. The third direction of the lab will be the MS-based screening of kinase targets using kinases with modified ATP-binding pockets. These methods enable the selective labeling of kinase targets in biological extracts using an ATP-analog designed to fit the modified kinase. We will perform a screen of kinases associated with cancer. Generally, kinases are difficult targets for small molecule drugs, since they are highly homologous. Instead, we will search for downstream substrates to identify novel cancer drug targets. |
| project group | ||||
|---|---|---|---|---|
| no | name | institution | position | |
| 1. | Mart Loog | Tartu Ülikooli Tehnoloogiainstituut | ||