Paul Cullen

Signal Transduction and Cell Polarity

Assistant Professor

Ph.D. (1990-1997) Washington University
Postdoc (1997-2004) University of Oregon
Assistant Professor (2004) University at Buffalo

 

Address Information

Dr. Paul Cullen
Department of Biological Sciences
625 Cooke Hall
State University of New York at Buffalo
Buffalo, NY 14260

(716) 645-2363 ext. 200

To send e-mail: pjcullen@buffalo.edu

Dr. Cullen's Supplemental Page

RESEARCH SUMMARY:

I am interested in understanding how signal transduction pathways function at the molecular level. Signal transduction pathways communicate information about the external environment to the inside of a cell. Signaling pathways also regulate cell polarity, and hence play a role in determining cell shape. Some of the responses governed by signaling pathways include changes to the cell cycle, changes to polarized growth, and changes to the transcriptional profile of the cell. Since these changes often trigger cancer in mammalian cells, understanding how signaling pathways function will provide insight into how pathways function improperly in cancer and other diseases. I use both mammalian cells and the model organism budding yeast to elucidate the relationships between signaling pathway activation and morphogenesis. Some of the signaling proteins I study are receptors (signaling mucins), GTPases, such as Cdc42, and kinases (PAK and MAPKs). One pathway that I focus on is the called the filamentous growth or FG pathway that directs changes in polarized growth in response to nutrient limitation. I also use a variety of approaches in the lab including genomics, biochemistry, genetics, and cell biology. Using these various models and techniques, I hope to gain mechanistic insight into the complexities of cellular signaling.

SELECTED PROJECTS:

Specificity of Cdc42-, PAK-, and MAPK-Pathways

A recent surprising finding is that signal transduction pathways share components. How does the activation of a pathway containing general factors induce a specific response? Indeed, inappropriate cross-talk between signaling pathways is a trigger for cancer. In yeast, the FG pathway, which is required for filamentous growth, is a composed chiefly of generic factors that function in multiple MAPK pathways. Few specific FG pathway components have been identified. Using genomic approaches, I discovered the presumptive receptor for the FG pathway, called Msb2. I am interested in understanding the mechanism whereby Msb2, which is a signaling mucin receptor communicates to Cdc42 and PAK to trigger activation of the FG pathway. Proteomic approaches (co-IP, MASS SPEC, 2-hybrid) will be used to identify protein-protein interactions at the head of the FG pathway. Moreover, characterizing the mucin receptor will ultimately result in elucidation of the ligand that triggers the FG pathway. Ultimately, these studies will lead to the design of drugs to receptors that induce filamentous growth in fungal pathogens.

 
     
Signaling pathway-dependent changes in cell polarity. In glucose-rich environments, yeast cells are spherical and grow towards each other (upper left panel). Glucose depletion triggers a change in cell polarity: cells are elongated and grow away from each other (upper right panel). Distinct polar landmarks are chosen, the cell cycle is extended, and the transcriptional and biochemical profile of the cell is altered. All of these changes are dependent on the FG pathway. Lower panel, the resultant morphology; a new cell type.  

Mammalian Mucins and Polarity

I discovered that loss of the mucin domain of Msb2 can trigger hyperactivation of the protein. This surprising result suggests that mucin-domain loss may trigger signal pathway activation and possibly cancer in mammalian cells. This result has broad implications in drug design and tumor diagnosis, and therefore I am beginning to extend my findings to mammalian systems. For example, do the mucin domains in metazoan signaling mucins inhibit pathway activity? Is there a correlation between mucin-domain deletion and metastasis in human tumors? I am also interested in the possibility that mammalian mucins play a role in cell polarity not previously appreciated. Using live-cell imaging of tissue culture cells I hope to watch the effects of mammalian mucin activation on the actin cytoskeleton in the cell.

 
     
  How do cells move, change their shape, and reorganize polarity in a dynamic fashion?  

New Connections to MAPK Pathways

I am interested in identifying new connections to the Msb2-Cdc42/PAK-MAPK pathway that controls filamentous growth in yeast. We are currently performing a variety of traditional and high-throughput genetic screens and we anticipate the identification of a number of factors, including scaffolding proteins, negative regulators, and modulators of Cdc42 activity. The most provocative connection I have found links the cell cycle at M phase/Start to MAPK activation and is governed by the mitotic exit network and cytokinesis.

 
     
  Genomic tools, such as DNA Microarray analysis are useful in the identification of new signaling pathway components as well as illuminating complex relationships between cellular pathways and processes.  

Cell-cell Adhesion, Cellular Invasion, and Biofilm Formation

Many interesting questions surround the FG pathway that I am beginning to explore. For example, FG occurs on a solid surface but not in liquid culture - how does this discrimination occur? Perhaps the receptor for the FG pathway plays a role in detecting this environment. Another avenue of investigation is the outputs of the FG pathway, which include cell-cell adhesion, invasion of cells into substrate, and cell migration (microbial biofilm formation). Understanding these processes has general applications to cancer (i.e. cellular invasion and adhesion) and to fungal pathogenesis. Bioinformatics approaches comparing genomes of budding yeast to true filamentous fungi will be used to identify conserved mechanisms that contribute to FG across species.

 
     
  Localization of a protein required for the axial budding pattern. Bud4p fused to green fluorescence protein (GFP) was visualized in live cells. Although the budding pattern of yeast cells changes when they are shifted from glucose rich to glucose limiting conditions, the localization of Bud4p does not change  

PUBLICATIONS: