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Researchers Discover Mechanism to Control Multiple Processes of Cell Growth, Division

March 23, 2015
Lebanon, NH

Dartmouth investigators explore molecular level of cell coordination in cancer

Investigators from Dartmouth's Norris Cotton Cancer Center led by James Moseley, PhD have found that the protein Pom1 possesses the ability to modify different sets of proteins to coordinate the processes of cell growth and division. Their paper, "Quantitative phosphoproteomics reveals pathways for coordination of cell growth and division by the fission yeast DYRK kinase Pom1," was published in Journal of Molecular and Cellular Proteomics.

cell proteins cancer

Chemical genetic inhibition of Pom1 causes a cell division protein, colored green in these pictures, to mis-localize to cell ends (left panel: no inhibition. right panel: Pom1 inhibited)

"Our biological question is how cells coordinate growth and division," explained Moseley. "For investigators working in cancer, this is an essential question. All cells grow for a while, and then they decide that it is time to divide – how do they coordinate these processes? What goes wrong at the molecular level when cells lose this coordination in diseases such as cancer?"

Moseley, a cell biologist, teamed with the laboratories of Scott Gerber and Arminja Kettenbach to utilize their proteomics expertise. Together, the collaborative team investigated a protein called Pom1 that functions in both growth and division. They hypothesized, since Pom1 was part of both processes, that it might be an important factor in coordinating the processes. In this current study, they learned Pom1 is not just a participant, it is a master regulator.

Complex phosphorylation-dependent signaling networks underlie the coordination of cellular growth and division. Pom1 is a kinase, meaning it puts a small tag (called phosphorylation) on other proteins which can then change the activity of the targeted proteins. Until now, no one knew what proteins were targeted by Pom1.

The Dartmouth team identified the main targets of Pom1 in cells and found it phosphorylates two sets of proteins: one set controls growth, and the other controls division. The study demonstrated that Pom1 acts in a linear pathway to control cell cycle progression while regulating a complex network of cell growth targets. Using Moseley's genetics expertise, the team controlled Pom1 activity very closely. They combined that tight control with Gerber and Kettenbach's experience in proteomics to search broadly for phosphorylation all throughout the Pom1 cells. This "team science" approach facilitated a comprehensive and unbiased view of the cells.

Looking forward, the team is moving in two directions. First, they will use the techniques established in this paper to identify the phosphorylation targets of other kinases. They also plan to examine more closely the Pom1 phosphorylation targets in cells to learn when and where they are getting phosphorylated by Pom1, and how the phosphorylation affects their activity.

"We are poised to figure out how Pom1 knows when to promote growth and when to promote division," said Kettenbach. "These are the types of processes that get uncoordinated in cancer cells and our plan is to pursue these key principles in our future work."

Moseley and Kettenbach each hold the rank of Assistant Professor in Dartmouth's Geisel School of Medicine Department of Biochemistry where Gerber is Associate Professor of Genetics, and of Biochemistry. Their cancer work is facilitated by Dartmouth's Norris Cotton Cancer Center where all are Members of the Cancer Mechanisms Research Program.

 "Quantitative phosphoproteomics reveals pathways for coordination of cell growth and division by the fission yeast DYRK kinase Pom1" was funded by the National Institutes of Health grant RO1-GM099774, RO1-CA-155260, and a grant from the Pew Charitable Trusts.

About Dartmouth-Hitchcock Norris Cotton Cancer Center

Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.

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