Yale Scientists Decipher 'Wiring Pattern' Of Cell Signaling Networks

The study is a breakthrough in understanding mechanisms of how proteins operate in different cell types under the control of master regulator molecules called protein kinases. Although protein kinases are already important targets of cancer drugs including Gleevec and Herceptin, until recently, it has been difficult to identify the proteins regulated by the kinases.

Led by Michael Snyder, Lewis B Cullman Professor of Molecular, Cellular and Developmental Biology, these researchers focused on the expression and relationship between proteins of the yeast cell "proteome," or the proteins that are active in a cell.

Protein kinases act as regulator switches and modify their target proteins by adding a phosphate group to them. This process, called "phosphorylation," results in altered activity of the phosphorylated protein. It is estimated that 30% of all proteins are regulated by this process.

Using technology developed in Snyder's laboratory, graduate students Jason Ptacek and Geeta Devgan used proteome microarrays to assay the thousands of different proteins in a yeast cell for targets of the protein kinases. The 82 unique kinases, representing the majority of master regulators in the yeast cell, were tested separately with the microarrays to determine which proteins were modified by each kinase.

From the wealth of information generated by these experiments Snyder's team constructed a complex map of the regulatory networks governing the functions and activities of the kinases in the yeast cell. The map shows several distinct patterns.

"It was a little like having all the pieces of an airplane separated out, and not knowing how those pieces function together to create an airplane and make it fly," said Snyder. "We wanted to know how the tens of thousands of proteins coordinate to carry out complex processes such as growth, cell division and formation of complex cell types such as brain cells and intestinal cells."

Over the past several years, a large volume of information on genes in organisms as diverse as man, mouse, baker's yeast and viruses has been generated. While genomic DNA is the blueprint, the encoded proteins are the products that carry out the complex biological functions of cells. Although scientists can predict from the DNA what proteins are in the proteome of an organism, this study opens the door to seeing how they are coordinated to work together.

"This insight into the regulation and integration of biological networks has broad applications for basic science and clinical research," said Snyder. "Biological networks determine the development and function of organisms from the single-celled yeast to man; aberrations in those networks signal disease."

Biological networks are typically conserved between species, meaning that often the same type of protein carries out the same type of function, whether it is in a yeast cell or a human cell. According to Snyder, these findings in yeast are of immediate use for understanding both human development from the fertilized egg to full grown organism, and for drug discovery targeting human diseases.

Other authors on the paper are Heng Zhu, Xiaowei Zhu, Joseph Fasolo, Ghil Jona, Soo-Jung Lee, Mark Gerstein and David F. Stern from Yale; Gregory Michaud, Hong Guo, Lihao Meng, Barry Schweitzer and Paul F. Predki from Invitrogen Corporation; Ashton Breitkreutz, Richelle Sopko, Michael Tyers and Brenda Andrews from the University of Toronto; Rhonda R. McCartney and Martin C. Schmidt from the University of Pittsburgh; Najma Rachidi and Michael J.R. Stark from the University of Dundee, UK; Angie S. Mah from the California Institure of Technology and Claudio DeVirgilio from the University of Geneva, Switzerland. The research was funded by grants from the National Institutes of Health, the Canadian Institutes of Health Research and the Wellcome Trust, UK.

Citation: Nature 439: (December 1, 2005)