Pharmacological approaches to understanding protein kinase signaling networks

Abstract

Protein kinases play vital roles in controlling cell behavior, and an array of kinase inhibitors are used successfully for treatment of disease. Typical drug development pipelines involve biological studies to validate a protein kinase target, followed by the identification of small molecules that effectively inhibit this target in cells, animal models, and patients. However, it is clear that protein kinases operate within complex signaling networks. These networks increase the resilience of signaling pathways, which can render cells relatively insensitive to inhibition of a single kinase, and provide the potential for pathway rewiring, which can result in resistance to therapy. It is therefore vital to understand the properties of kinase signaling networks in health and disease so that we can design effective multi-targeted drugs or combinations of drugs. Here, we outline how pharmacological and chemo-genetic approaches can contribute to such knowledge, despite the known low selectivity of many kinase inhibitors. We discuss how detailed profiling of target engagement by kinase inhibitors can underpin these studies; how chemical probes can be used to uncover kinase-substrate relationships, and how these tools can be used to gain insight into the configuration and function of kinase signaling networks.

Targeting Protein Kinases to Protect Beta-Cell Function and Survival in Diabetes

“…As examples, tyrosine kinase inhibitors are widely used in clinical oncology. Tyrosine kinase inhibitors target key mechanisms such as cell growth, invasion, metastasis, and angiogenesis (for reviews, see [ 52 , 53 , 54 ]). However, despite intensive research, the question of whether safe drugs that inhibit protein kinase activity can be designed and developed to protect beta-cell function and survival during T1D and T2D remains unresolved ( Figure 1 and Figure 2 ; Table 1 ).…”

“…The signal transduction is due to the reversible phosphorylation of proteins by modifying the structure and function. Protein kinases constitute a very extensive family of structurally bound enzymes that are involved in the control of cell growth, proliferation, differentiation, apoptotic death, cytoskeletal rearrangement, metabolic pathways, membrane transport, and motility [ 52 , 53 , 54 ]. Kinases usually have a catalytic domain with nucleotide and substrate binding sites, flanked by regulatory domains, inhibitor binding sites, and phosphorylation sites, and can undergo conformational rearrangements ( Figure 3 ).…”

“…To date, nearly 535 human protein kinases have been identified [ 53 , 54 ]. The two main classifications based on the enzymatic activities are the serine/threonine kinase proteins that phosphorylate proteins on serine/threonine residues, and the tyrosine kinase proteins that phosphorylate proteins on tyrosine residues [ 52 , 53 , 54 ]. Beyond their phosphorylation functions, protein kinases exhibit non-catalytic functions such as the formation of complex protein scaffolding and binding to DNA [ 58 ].…”

“…Genetic alteration and modification of the protein kinase functions are linked to cancer and immunological, neurological, cardiovascular, and metabolic diseases [ 52 , 53 , 54 ]. Therefore, protein kinases are considered to be important clinical targets for the treatment of various diseases.…”

“…In vitro [57] Protein kinases are ubiquitous intracellular and cellular surface proteins with enzymatic properties. Protein kinases selectively catalyze protein phosphorylation by the transfer of a phosphate group from ATP, GTP, and other phosphate donors to the -OH group of amino acids (threonine, serine, and tyrosine) in protein substrates, allowing conformational changes from an inactive to an active form (for reviews, see [52][53][54]). The signal transduction is due to the reversible phosphorylation of proteins by modifying the structure and function.…”