Yale Scientists Decipher 'wiring Pattern' Of Cell Signaling Networks

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Yale Scientists Decipher 'wiring Pattern' Of Cell Signaling Networks

http://www.medicalnewstoday.com/medicalnews.php?newsid=34393

A team of scientists at Yale University has completed the first

comprehensive map of the proteins and kinase signaling network that

controls how cells of higher organisms operate, according to a report

this week in the journal Nature.

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 Snyder, 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

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, ph Fasolo,

Ghil Jona, Soo-Jung Lee, Mark Gerstein and F. Stern from Yale;

Michaud, Hong Guo, Lihao Meng, Barry Schweitzer and F.

Predki from Invitrogen Corporation; Ashton Breitkreutz, Richelle

Sopko, Tyers and s from the University of

Toronto; Rhonda R. McCartney and C. Schmidt from the

University of Pittsburgh; Najma Rachidi and 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)

Yale University

http://www.yale.edu