SC Connecticut News

"In the human body, molecules known as kinases propagate signals within and between cells, relaying signals that allow cells to respond to changes in the environment. But there are hundreds of different kinases in the body, and identifying their individual and collective functions is challenging."

"In a new study, Yale pharmacologist Benjamin Turk and his colleagues developed tools that can help researchers hone in on the roles of individual kinases and begin to uncover a more complete picture of their collective contribution to biological function."

"And because dysfunctional kinases are often implicated in cancer, a more refined understanding of their function may yield better treatments in the future, they say."

"The findings were published May 8 in Nature."

"Understanding how tyrosine kinases signal is key to understanding how cells communicate with each other, with that communication often being a signal to grow or divide."

"Benjamin TurkKinases are enzymes that facilitate a process called phosphorylation. In cases that involve proteins, a protein kinase recruits a piece of a molecule called a phosphate group (a molecular fragment consisting of a phosphorus atom and four oxygen atoms) and helps attach it to a specific area of a protein known as a phosphorylation site. This can change the protein’s function in a number of ways, altering its activity or where it travels, for example."

"There are two types of protein kinases depending on the proteins they phosphorylate: serine/threonine kinases, which Turk focused on in a previous study, and tyrosine kinases, the subject of the new study."

“Tyrosine kinases in particular are really important for cell-to-cell and organ-to-organ communication,” said Turk, associate professor of pharmacology at Yale School of Medicine. “The major class of tyrosine kinases is associated with growth factors. Understanding how tyrosine kinases signal is key to understanding how cells communicate with each other, with that communication often being a signal to grow or divide.”

"All types of tyrosine kinases — of which there are 78 in humans — tend to over-send growth signals when they become hyperactivated, which is a key event in tumor growth, says Turk."

“This kind of study helps us understand the organization of tyrosine kinase signaling, which gives us insight into how kinases send growth signals and how blocking kinases might lead to a therapeutic response,” he said."

"For the study, the researchers first looked at how kinases recognize their targets. Proteins are made up of amino acids, of which there are 20; kinases recognize short strings of amino acids that surround the site they phosphorylate."

"And, importantly for treatment development, the tools developed in this study allow the researchers to infer which kinases might be active in a cell or tissue at a particular time and how perturbing them might affect their function."

“With their tools, the researchers can observe how blocking one kinase with an inhibitor sometimes leads to other kinases becoming overactivated, which may explain how cancer cells adapt and continue to grow. And that can help researchers develop more effective therapies,” said Turk."

"Going forward, Turk aims to use the rules uncovered in this work to start teasing apart key biological processes and to look further into how different cells respond to various kinase inhibitors."

"Tyrosine kinases are newer, evolutionarily speaking, than other kinases, emerging with multicellular organisms. When Turk and his colleagues compared human tyrosine kinases to those in nematodes — a type of worm that the human branch of the evolutionary tree diverged from millions of years ago — the specificity of both groups of kinases, or how particular they are about their targets, were extremely similar."

“That says this specificity — and understanding how it occurs — really matters,” said Turk. “It’s conserved throughout millions of years of evolution and nature would not have maintained it in such fine detail without reason.”"""