New Enzyme ‘Atlas’ Unlocks Secrets of Cellular Pathways for Researchers

According to Science Daily, protein kinases are one of the essential family enzymes in the human body, acting as signaling molecules to govern vital cellular processes such as proliferation, differentiation, and metabolism. Disruptions in these biological mechanisms have been linked to various illnesses, including cancer.  

However, little is known about the physiological pathways these kinases engage or the substrates on which they act. Learning about the protein kinases that contribute to cellular dysfunction and cancer formation might lead to identifying new therapeutic targets. “Even though cancer genome sequencing efforts have yielded a plethora of knowledge, further research is required to study signaling pathways and protein kinase activation states properly.

Such knowledge might lead to more accurate therapeutic targeting of cancers.” Dr. Michael Yaffe, head of MIT’s Center for Precision Cancer Medicine and a senior member of the Koch Institute for Integrative Cancer Research, is one of the study’s senior authors.  

Researchers now have a thorough inventory of the more than 300 protein kinases found in human cells, as well as an understanding of which proteins each kinase is predicted to target and regulate, thanks to the research of Yaffe and colleagues. This knowledge might help scientists understand how cancer cells develop and how certain medications affect cellular communication.  

More than 500 protein kinases are encoded in the human genome, enzymes that change other proteins’ activity by adding or removing phosphate groups. Even though research into kinases like MEK and RAF, vital in cellular pathways that promote development, has led to new cancer medicines that inhibit those kinases, the proteins that most kinases target remain a mystery.  

Researchers may learn whether cancer cells or healthy cells have a higher rate of protein phosphorylation by applying mass spectrometry (the process of separating molecules based on their mass and charge) to the study of phosphoproteomics and thus uncover novel pathways that are dysregulated in cancer.

However, it was previously challenging to query mass spectrometry data to establish which protein kinases phosphorylate the targets. As a result, the mechanisms by which these proteins are regulated in the case of sickness have remained unknown.  

Most phosphopeptides have not yet been assigned to a recognized signaling pathway. No Rosetta stone would allow people to look at these peptides and confidently declare. This is the pathway that the data is telling us about. This is because we need to know what substrates are for most protein kinases.  

Yaffe has been captivated by protein kinases and their involvement in signal transduction from his days as a postdoc in Cantley’s group 25 years ago. Turk soon joined the group; the three have spent decades investigating these enzymes individually.  

“This is a cooperation that began 25 years ago when Ben and I were in Lew’s lab, and it’s finally actually coming together, thanks in large part to what the lead authors, Jared and Tomer, did,” Yaffe explains. Serine and threonine kinases, which account for over 85% of all protein kinases in the human body, were divided in this study based on the structural motif to which phosphate groups were added.

Cantley and Turk’s collection of kinase-interacting patterns was used to investigate peptide interactions with all 303 known serine and threonine kinases. The researchers utilized a computer model to examine the observed connections and determine the particular kinases that phosphorylate each of the 90,000 reported phosphorylated cellular sites. 

Researchers discovered that several kinases with vastly varied amino acid sequences converge on the same substrate patterns for binding and phosphorylation. Furthermore, they discovered that about half of the kinases studied belong to only one of a dozen pattern classes.

Yaffe argues that the novel kinase atlas may be used to distinguish between normal and malignant cells and between treated and untreated cancer cells by providing light on the critical signaling pathways. He claims that the kinase motif atlas has helped him comprehend signaling networks. While there are many phosphorylated peptides, we can identify the kinase that first phosphorylated each.  

They examined cells that had been pretreated with an anticancer treatment that suppresses the activity of Plk1, a kinase that regulates cell division, to demonstrate the efficiency of this technique.

Plk1 was predicted to be discovered to regulate the production of numerous other phosphoproteins. Surprisingly, they also discovered an increase in the expression of two kinases (protein kinases) involved in the physiological response to DNA damage.  

Yaffe’s team wants to use it to identify other defective signaling pathways that promote cancer growth, particularly in malignancies with no genetic drivers.

He believes phosphoproteomics can help us make informed judgments about whether a patient’s tumor has up or downregulated specific pathways. When the genetic etiology of cancer is unknown, scientists may explore “signaling pathways that drive cancer,” as the authors put it.