Many essential signaling processes in animal cells are mediated by enzymes that phosphorylate and dephosphorylate tyrosine residues on proteins as a means of relaying information. These enzymes, known as protein tyrosine kinases and protein tyrosine phosphatases, play a crucial role in normal animal physiology and are often dysregulated in diseases such as cancers and immunological disorders. As a result, these enzymes are important drug targets.
There are ~100 members of the tyrosine kinase and tyrosine phosphatase families, and we are inspired by the evolution of the complex signaling networks that they control. Our goal is to integrate chemical approaches with high-throughput biochemical assays, biophysical methods, and evolutionary analyses to pinpoint (1) how individual members of these enzyme families have specialized to mediate signal transduction with fidelity, (2) how the dysregulation of phosphotyrosine signaling enzymes leads to disease states, and (3) how we might exploit this information to guide the development of novel therapies.
Neel H. Shah, Mark Löbel, Arthur Weiss, and John Kuriyan. “Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen.” eLife (2018), 7, e35190.
Pradeep Bandaru, Neel H. Shah, Moitrayee Bhattacharyya, John P. Barton, Yasushi Kondo, Joshua C. Cofsky, Christine L. Gee, Arup K. Chakraborty, Tanja Kortemme, Rama Ranganathan, and John Kuriyan. “Deconstruction of the Ras switching cycle through saturation mutagenesis.” eLife (2017), 6, e27810.
Neel H. Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A. Kadlecek, Ian R. Fallahee, William P. Russ, Rama Ranganathan, Arthur Weiss, and John Kuriyan. “An Electrostatic Selection Mechanism Controls Sequential Kinase Signaling Downstream of the T Cell Receptor.” eLife (2016), 5, e20105.
Neel H. Shah, Ertan Eryilmaz, David Cowburn, and Tom W. Muir. “Naturally Split Inteins Assemble through a ‘Capture and Collapse’ Mechanism.” Journal of the American Chemical Society (2013), 135, 18673-18681.
Miquel Vila-Perelló, Zhihua Liu, Neel H. Shah, John A. Willis, Juliana Idoyaga, and Tom W. Muir. “Streamlined Expressed Protein Ligation Using Split Inteins.” Journal of the American Chemical Society (2013), 135, 286-292.
Neel H. Shah, Geoffrey P. Dann, Miquel Vila-Perelló, Zhihua Liu, and Tom W. Muir. “Ultrafast Protein Splicing is Common among Cyanobacterial Split Inteins.” Journal of the American Chemical Society (2012), 134, 11338-11341.
Neel H. Shah, Glenn L. Butterfoss, Khanh Nguyen, Barney Yoo, Richard Bonneau, Dallas L. Rabenstein, and Kent Kirshenbaum. “Oligo-(N-aryl glycines): A New Twist on Structured Peptoids.” Journal of the American Chemical Society (2008), 130, 16622-16632.