Comprehensive Kinase Atlas Reveals New Insights Into Cell Signaling And Disease

The enzyme RNA polymerase II transcribes genes into messenger RNA. This process is guided by modifications to nan enzyme's "tail" called phosphorylation patterns. Scientists astatine St. Jude Children's Research Hospital explored these patterns, identifying 117 kinases that could phosphorylate aggregate locations wrong nan macromolecule tail. This greatly expands upon nan group of kinases antecedently known to phosphorylate RNA polymerase II. The activity besides links nan enzyme's activity to aggregate diseases, including cancer, for example, done nan cell-surface tyrosine kinase EGFR, which was shown to phosphorylate RNA polymerase II successful nan nucleus. EGFR is prominently mutated successful lung cancer. The findings were published coming in Science.

RNA polymerase II's tail is composed of repeats of nan aforesaid 7 amino acids. Cells power chopped steps of cistron transcription utilizing kinases, which connect phosphate groups onto this repeated amino acerb sequence, peculiarly astatine positions 2 and five. The relevance of nan different 5 amino acids to RNA polymerase II usability has been debated.

Aseem Ansari, St. Jude Department of Chemical Biology & Therapeutics chair, sought to explain this uncertainty. "We knew location were kinases beyond nan canonical ones, but appreciated that specificity often comes from proximity," Ansari said. "Many kinases tin phosphorylate nan tail, truthful we wanted to benignant done them to find which are meaningful." 

Cell aboveground kinase delivers connection to nan nucleus

The researchers tested 427 kinases to spot if, really and wherever they could phosphorylate nan RNA polymerase tail, pinch Ansari crediting nan value of nan infrastructure disposable astatine St. Jude for specified an undertaking. "The study would not person been imaginable without nan unthinkable shared and departmental resources that are disposable to scientists astatine St. Jude," he said. They identified 117 kinases pinch a important penchant for phosphorylation location. This included antecedently disregarded positions, arsenic 54 of nan tested 62 tyrosine kinases acted exclusively astatine position one. 

Within this broad kinase atlas were immoderate unexpected findings relating to cell signaling. "The astir improbable thought was that a compartment aboveground receptor kinase specified arsenic EGFR could phosphorylate RNA polymerase II," said Ansari. "To my surprise, our imaging information showed nan receptor successful nan nucleus, thing which has been reported for decades, but marginalized. Our grounds confirmed this, and now we tin yet explicate why." 

Exhaustive experimentation confirmed that RNA polymerase II phosphorylation astatine position 1 by EGFR was required for transcription. This carries important implications for really compartment signaling is perceived. 

People deliberation of compartment signaling arsenic a relay of kinases that past enactment connected a transcription factor, but our information tells america it's much integrated than that. Signaling tin beryllium much immediate, arsenic signaling kinases are not waiting for transcription factors to find their home. They tin get to nan tract and power nan process much directly."

Aseem Ansari, St. Jude Department of Chemical Biology & Therapeutics chair

The study greatly expands connected RNA polymerase II phosphorylation patterns and supports further exploration of their individual relevance. It besides creates a nexus betwixt phosphorylation of nan enzyme's tail and diseases specified arsenic cancer. 

"Some fierce cancers person kinases untethered successful nan nucleus, disrupting transcriptional programs," Ansari explained. "We've been ignoring these kinases successful nan nucleus because it's a mini fraction of nan signal; nan expectations were that signaling is happening astatine nan compartment surface. But by shifting wherever we comprehend nan therapeutic vulnerability, this changes really we deliberation astir pathology."

Authors and funding

The study's first writer is Preeti Dabas, St. Jude. The study's co-second authors are Meritxell Cutrona and Wojciech Rosikiewicz, St. Jude. The study's different authors are Ryan Kempen, Patrick Rodrigues, John Bowling, Mollie Prater, Walter Lang, Adithi Danda, Zhi Yuan, Beisi Xu, Shondra Pruett-Miller, Gang Wu and Taosheng Chen, St. Jude.

The study was supported by nan National Cancer Institute (P30 CA021765) and nan American Lebanese Syrian Associated Charities (ALSAC), nan fundraising and consciousness statement of St. Jude.