Department of Cell Biology Faculty

Regulation of Signaling Molecules important for Development, Cell Cycle and Growth

Yeast sexual differentiation provides a relatively simple system for exploring how environmental cues are sensed and interpreted through intracellular signaling mechanisms. In Schizosaccharomyces pombe, conjugation and meiosis are regulated by mating-pheromone and nutrient-sensing signals through Ran1p protein kinase. Ran1p is active during mitotic cell division and inhibits differentiation by phosphorylating and inactivating key substrates required for conjugation and meiosis. Meiosis is promoted by complete inactivation of Ran1p through physical association with the Mei3p inhibitor. Our laboratory has studies interactions between Ran1p and the Mei3p. These studies i) Identified a Ran1p-binding domain in Mei3p. ii) Identified Ste11p substrate specificity determinants (a key substrate for Ran1p) and iii) Identified regions of both Ste11p and Mei3p that function in localization of each protein. One important finding was that the cellular localization of Ste11p is dynamic and is regulated by both nutrient and pheromone signaling. Current research is focused on defining the molecular mechanics regulating Ste11p localization.

Ste11p is a member of the HMG family of DNA-binding proteins, which includes the mammalian sex determining factor, SRY, and the related SOX genes. Deregulation of SOX genes is frequently associated with human disease, including malignancy. The subcellular localization of some HMG box proteins is regulated by cell type, presumably in response to hormonal signaling. For instance, SOX9 functions in sex determination. SOX9 is nuclear in developing male gonads but cytoplasmic in developing female gonads. It is widely believed that localization of some HMG box proteins is an important mechanism to regulate their activity. Our goals are to describe the mechanisms that direct the distribution of HMG box proteins to specific subcellular compartments, and to determine how external signals regulate their ability to activate target gene expression.

The subcellular distribution of Ste11p is dynamic in cells engaged in conjugation and meiosis

PUBLICATIONS

• Li, P. and McLeod, M. (1996). Molecular Mimicry in Development: Identification of ste11+ as a Substrate and mei3+ as a Pseudosubstrate Inhibitor of ran1+ Kinase. Cell 87:869-880.
• Wang, W., Li, P., Schettino, A., Peng, Z. and McLeod, M. (1998). Identification of Mei3 Motifs Required for Induction of Meiosis and Inhibition of Ran1 Kinase In Vitro. Genetics 150:1007-1018.
• McLeod, M., Shor, B., Caporaso, A., Wang, W., Chen, H. and Hu, L. (2000). Cpc2, a Fission Yeast Homologue of Mammalian RACK1 Protein, Interacts with Ran1/Pat1 Kinase to Regulate Cell Cycle Progression and Meiotic Development. Mol. Cell. Biol. 11:4016-4027.
• Qin, J., Kang, W., Leung, B. and McLeod, M. (2003). Ste11p, and HMG box DNA-binding protein, undergoes pheromone and nutrient regulated nuclear-cytoplasmic shuttling. Mol. Cell. Biol (accepted for publication).
• Peng, Z., Wang, W.,Schettino, A., Leung, B. and McLeod, M. (2003). Inactivation of Ran1/Pat1 Kinase Bypasses the Requirement for High-Level Expression of mei2 During Fission Yeast Meiosis. Curr. Genet. (accepted for publication).

LABORATORY PERSONNEL

Boris Shor

Jian Qin

Zhe Peng

Kun Cai

Yi Tang

Wenfei Kang

Betty Leung

EDUCATION

Ph.D; 1984 SUNY Stony Brook