Kinetics and Regulation of Protein Kinases
Piala, Alexander Townshend
MetadataShow full item record
One of the major functions of kinases in biological systems is the relay of signal from an effector to a downstream target. Kinases are regulated by a diversity of mechanisms, both internal and external to the kinase. When the regulation of these kinases is somehow abrogated, disease can result. As such, understanding of these regulatory mechanisms could serve as useful in not only understanding cellular signal propagation, but also the disease states that can arise from their malfunction. Taking advantage well-developed projects in the Goldsmith lab, three systems were studied: two kinases and one kinase cascade. The MAP3K Thousand and One Kinase 2 was the subject of an inhibitor discovery program using high-throughput screening of a large small-molecule library. Secondly, the mechanism by which the kinase With No Lysine(K) 1 responds to chloride concentration in order to modulate downstream signaling was studied. Finally, a cascade comprising the MAP3K Apoptosis Signaling Kinase 1, MAP/ERK Kinase 6, and p38a was studied through modeling approaches using data derived from mass spectrometry. In each case, mechanisms for regulation were discovered. Tight-binding inhibitors of TAO2 were found that may prove useful in both in in vitro signaling studies as well as future in vivo work. WNK1 was shown to be regulated by direct chloride binding, which inhibits its auto-phosphorylation and thusly its auto-activation. Finally, important kinetic parameters for MAPK cascade signaling were determined, and it was demonstrated that additional species outside the cascade do not appear necessary for switch-like behavior under physiological-like in vitro conditions. These diverse regulatory mechanisms showcase how protein kinases manage to synthesize diverse inputs into physiologically meaningful downstream signals.
Showing items related by title, author, creator and subject.
Identification of Intracellular Signaling Pathways Regulated by the TAO Family of Mammalian STE20p Kinases Raman, Malavika (2006-05-16)TAO1, 2 and 3 are a sub-family of mammalian Ste20p protein kinases. They have been shown to regulate activation of p38 MAPK by phosphorylating and activating MEK3 and 6. Little is known about the precise cellular roles for ...
Taylor, Clinton A., IV; 0000-0002-8283-3393 (2016-12-07)Protein-protein interactions are essential for nearly every cellular process. Within signaling pathways, such interactions carry out numerous functions such as defining substrate specificity, inhibition of both other ...
Franco, Jorge (2016-06-06)Pancreatic ductal Adenocarcinoma (PDA) is an aggressive and lethal disease that lacks an adequate treatment. Given that patients with PDA only marginally benefit from the current therapies, there is an urgent need to develop ...