Dynamic regulatory features of the protein tyrosine kinases

Abstract

The SRC, Abelson murine leukemia viral oncogene homolog 1, TEC and C-terminal SRC Kinase families of non-receptor tyrosine kinases (collectively the Src module kinases) mediate an array of cellular signaling processes and are therapeutic targets in many disease states. Crystal structures of Src modules kinases provide valuable insights into the regulatory mechanisms that control activation and generate a framework from which drug discovery can advance. The conformational ensembles visited by these multidomain kinases in solution are also key features of the regulatory machinery controlling catalytic activity. Measurement of dynamic motions within kinases substantially augments information derived from crystal structures. In this review, we focus on a body of work that has transformed our understanding of non-receptor tyrosine kinase regulation from a static view to one that incorporates how fluctuations in conformational ensembles and dynamic motions influence activation status. Regulatory dynamic networks are often shared across and between kinase families while specific dynamic behavior distinguishes unique regulatory mechanisms for select kinases. Moreover, intrinsically dynamic regions of kinases likely play important regulatory roles that have only been partially explored. Since there is clear precedence that kinase inhibitors can exploit specific dynamic features, continued efforts to define conformational ensembles and dynamic allostery will be key to combating drug resistance and devising alternate treatments for kinase-associated diseases.

Bruton’s Tyrosine Kinase Targeting in Multiple Myeloma

“…Protein kinases (PTKs) act like a person flipping a molecular switch to control whether proteins are turned on or off. Kinases accomplish this by facilitating the transfer of a phosphate group from ATP to either a serine, threonine or tyrosine residue of their target protein [ 7 , 8 ]. BTK is one of the five Tec family kinases, a group of cytosolic kinases that phosphorylate tyrosine residues.…”

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction

“…However, ADAM15 has an active metalloproteinase domain which could cleave cell surface receptors that are required for optimal AM activation. In addition, ADAM15 has a cytoplasmic tail that can bind intracellular proteins including Src kinases [ 11 ] which have diverse activities in regulating cell activation and survival [ 40 ].…”

The Protein Tyrosine Kinase Inhibitor Genistein Suppresses Hypoxia-Induced Atrial Natriuretic Peptide Secretion Mediated by the PI3K/Akt-HIF-1α Pathway in Isolated Beating Rat Atria

“…PTKs are important enzymes that catalyze substrate protein phosphorylation, where they transmit extracellular signals to the intracellular space and activate various intracellular signaling pathways that regulate processes of cell growth, differentiation, metabolism, migration, and apoptosis [24]. Also, studies suggested that they control the abnormal signaling transduction of cells under ischemia conditions [25][26][27].…”