Cullin 2-RING ubiquitin ligase (CRL2) complexes target proteins for degradation to control dynamic cellular processes including the cell cycle, polarity, and signal transduction. This proposal focuses on understanding the molecular pathways that regulate how CRL2 complexes control: the actin cytoskeleton and cell motility;the Ras and Notch signaling pathways;and the mitotic regulator cyclin B. These CRL2-regulated pathways have important implications for the control of cell proliferation, development, and cancer.
Aim 1 focuses on CRL2-mediated regulation of the CDK-inhibitors p21Cip1 and p27Kip2 in the cytoplasm. CRL2LRR1 targets the degradation of cytoplasmic p21 to control actin cytoskeletal dynamics and cell motility. Proposed experiments address the regulation of p21 binding to CRL2LRR1, and the mechanism by which certain oncogenes circumvent CRL2LRR1-mediated degradation of p21. A distinct CRL2 complex regulates cytoplasmic p27 levels through an indirect mechanism by negatively regulating the levels of the Ras pathway effectors RSK1 and RSK2. Experiments address how the degradation of RSK1/2 is regulated;the functional consequences of the degradation;and the identification of the substrate-recognition subunit for the CRL2 complex.
Aim 2 seeks to identify the molecular pathway by which CRL2LRR-1 represses Notch signaling in the developing C. elegans vulva, through the use of genetic analysis in combination with reporter transgenes.
Aim 3 focuses on the paradigm-shifting observation that the mitotic regulator cyclin B is targeted for degradation not only by the APC/C complex (which is currently regarded as the sole ubiquitin ligase for cyclin B degradation) but also by the CRL2ZYG-11 complex. The cyclin B-CDK1 complex is the key cell cycle regulator that drives cells into mitosis;and the degradation of cyclin B is essential for mitotic exit. Discovering how the degradation of cyclin B is regulated is critical for understandin the overall regulation of mitosis. The experiments in this aim will characterize the interaction of cyclin B with CRL2ZYG-11, determine the mechanism through which the degradation is cell cycle regulated, and explore whether the pathway is conserved in mammals.
Metastatic cancer is caused by the unregulated proliferation of cells that are able to move throughout the body. This proposal addresses how CRL2 protein complexes (which degrade other proteins) act to: inhibit the Ras and Notch signaling pathway that promote cancer;block cell movements;and degrade a central regulator of cell division (cyclin B). This project will provide new insights into fundamental cancer-related processes, and provide the potential for the future development of cancer therapies.
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