New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome

Abstract

The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. .

The ribosome: A hot spot for the identification of new types of protein methyltransferases

“…The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins.…”

Activation of RyR2 by class I kinase inhibitors

“…Leading the way are small compounds designed to inhibit protein kinases involved in metabolism, cell survival and cell cycle progression. There are around 500 protein kinases present in the human kinome, and around 150 of them have been linked to the progression of various diseases including inflammatory diseases, cardiovascular diseases, metabolic diseases and cancer (Cohen, 2001;Wilson et al, 2018). Several strategies are employed to inhibit kinases pharmacologically, the most common being those that target the active conformation of the ATP-binding pocket; compounds termed class I kinase inhibitors.…”

Kinobead Profiling Reveals Reprogramming of B-cell Receptor Signaling in Response to Therapy Within Primary Chronic Lymphocytic Leukemia Cells

“…24 Other kinases with substantially reduced capture in drug treated cells included LCK, FYN, LYN, FGR, SRC, CSK, TEC, BLK and RIPK2, which are all known to be directly inhibited by both ibrutinib and dasatinib. 23,25,26 We also observed more modest reductions in capture of a number of other kinases including ERK1 and 2, PKCb and IKKb ( Figure 1D) which are not known as direct targets of ibrutinib/dasatinib but are likely to be modulated as a response to upstream effects. Reduced capture of MEK1 and MEK2 was consistent with the observed reduction of phosphorylation of the MEK1/2 substrates ERK1/2 detected by immunoblotting ( Supplementary Figure 1).…”

“…Ibrutinib and dasatinib are considered primarily as inhibitors of BTK and ABL, respectively, although both drugs have numerous additional kinase targets, some of which are shared. 23 Analysis was performed after 60 minutes of drug exposure; a time point at which we would not expect to observe substantial changes in the steady state expression of kinases. Thus, changes in kinase capture are likely to reflect both direct target engagement (thereby blocking kinobead binding) and secondary effects on downstream kinases.…”