What is Protein kinase (PK) family?

Protein kinases are key regulatory enzymes that change the properties of a substrate by attaching a phosphate group to Ser, Thr or Tyr residues. Protein kinases are among the largest families of genes in eukaryotes. Most protein kinases, a single superfamily containing a eukaryotic protein kinase catalytic domain, mediate most of the signal transduction in eukaryotic cells, by modification of substrate activity. As the essential effectors of cellular signaling, protein kinases also control many other cellular processes, including metabolism, transcription, cell cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation. Protein phosphorylation also plays a critical role in intercellular communication during development, in physiological responses and in homeostasis, and in the functioning of the nervous and immune systems. Mutations and dysregulation of protein kinases play causal roles in human disease, such as cancer, affording the possibility of developing agonists and antagonists of these enzymes for use in disease therapy.

Protein kinase family is divided into 3 main classes including AGC, CaMK, and CMGC.

-- AGC kinases

AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes. The subgroup of Ser/Thr protein kinases were defined, which based on sequence alignments of their catalytic kinase domain, were most related to cAMP-dependent protein kinase 1 (PKA; also known as PKAC), cGMP-dependent protein kinase (PKG; also known as CGK1α) and protein kinase C (PKC). AGC family kinase 1 is specifically involved in trogocytosis of live human cells and does not participate in phagocytosis of dead cells. EhAGCK1, one of the AGC family kinases, is specififically involved in trogocytosis but not in phagocytosis of dead cells, while EhAGCK2 is involved in all actin-dependent endocytic processes. The family of AGC kinases is known to influence actin dynamics by operating downstream of PI3K. Akt phosphorylates β-actin in a PtdIns(3,4,5)P₃-dependent manner, generally resulting in enhanced cell migration. Moreover, PKC phosphorylates myristoylated alanine rich C-kinase substrate, which plays a crucial role in F-actin cross-linking by integrating the signalling from PKC and calcium-calmodulin.

Figure 1 Mechanisms of activation of Akt

-- CaMK kinase

Ca²⁺/calmodulin activates multifunctional CaMKs, a family of serine/threonine protein kinases that include CaMKI, CaMKII and CaMKIV. CaMKII is abundantly expressed in neurons and is indispensable for the generation of synaptic plasticity such as longterm potentiation. CaMKIV is important in brain functions such as long-term memory, mainly by activating CREB-dependent transcription through its phosphorylation. Ca²⁺/calmodulin dependent kinases (CaMKs) activate downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB). The inhibition of CaMKs as well as the genetic ablation of Camk4 reduce CREB phosphorylation and downregulate the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis). The CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced.

Figure 2 Schematic diagram of biphasic regulation of osteoclastic bone resorption by the CaMKIV-CREB pathway

-- CMGC kinase

Both Homeodomain-interacting protein kinases (HIPKs) and Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) belong to the CMGC group of serine/threonine kinases. HIPKs are an evolutionarily conserved kinase family comprising the members HIPK1, HIPK2, and HIPK3 in vertebrates, and, additionally, HIPK4 in mammals, which are closely related to dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) that includes cyclin-dependent kinases (CDKs), mitogen-activated kinases (MAPKs), glycogen synthase kinases (GSK) and CDK-like kinases (CLKs). HIPKs, which can phosphorylate a variety of targets including numerous transcription factors, are regulators of various signaling pathways and involved in the pathology of cancer, chronic fibrosis, diabetes, and multiple neurodegenerative diseases. The targeting of DYRK1A or HIPKs may contribute to the transcriptional inhibition and therapeutic activity of drug inhibitor in cancer.

Protein kinases are highly versatile executioners of signal transduction networks, which influence an array of biological responses of great relevance to our understanding of health and disease, such as cancer, diabetes, etc. The colocalization of protein kinases with their substrates and upstream activators is crucial for the treatment of the disease, which contributes to find the right drug therapy target.