Protein Kinase-Mediated Decision Between the Life and Death.

Protein kinases are intracellular signaling enzymes that catalyze the phosphorylation of specific residues in their target substrate proteins. They play important role for regulation of life and death decisions. The complexity of the relationship between death receptors and protein kinases' cell death decision-making mechanisms create many difficulties in the treatment of various diseases. The most of fifteen different cell death pathways, which are reported by Nomenclature Committee on Cell Death (NCCD) are protein kinase signal transduction-mediated negative or positive selections. Tumor necrosis factor (TNF) as a main player of death pathways is a dual-functioning molecule in that it can promote both cell survival or cell death. All apoptotic and necrotic signal transductions are conveyed through death domain-containing death receptors, which are expressed on the surface of nearly all human cells. In humans, eight members of the death receptor family have been identified. While the interaction of TNF with TNF Receptor 1 (TNFR1) activates various signal transduction pathways, different death receptors activate three main signal transduction pathways: nuclear factor kappa B (NF-ĸB)-mediated differentiation or pro-inflammatory cytokine synthesis, mitogen-activated protein kinase (MAPK)-mediated stress response and caspase-mediated apoptosis. The link between the NF-ĸB and the c-Jun NH2-terminal kinase (JNK) pathways comprise another check-point to regulate cell death. TNF-α also promotes the "receptor-interacting serine/threonine protein kinase 1" (RIPK1)/RIPK3/ mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necrosis. Thus, necrosome is mainly comprised of MLKL, RIPK3 and, in some cases, RIPK1. In fact, RIPK1 is at the crossroad between life and death, downstream of various receptors as a regulator of endoplasmic reticulum stress-induced death. TNFR1 signaling complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of transforming growth factor β-activated kinase 1 (TAK1), inhibitor of nuclear transcription factor κB (IκB) kinase (IKK) α/IKKβ, IκBα, and NF-κB. IKKs affect cell-survival pathways in NF-κB-independent manner. Toll-like receptor (TLR) stimulation triggers various signaling pathways dependent on myeloid differentiation factor-88 (MyD88), Interleukin-1 receptor (IL-1R)-associated kinase (IRAK1), IRAK2 and IRAK4, lead to post-translational activation of nucleotide and oligomerization domain (NLRP3). Thereby, cell fate decisions following TLR signaling is parallel with death receptor signaling. Inhibition of IKKα/IKKβ or its upstream activators sensitize cells to death by inducing RIPK1-dependent apoptosis or necroptosis. During apoptosis, several kinases of the NF-κB pathway, including IKK1 and NF-κB essential modulator (NEMO), are cleaved by cellular caspases. This event can terminate the NF-κB-derived survival signals. In both canonical and non-canonical pathways, IKK is key to NF-κB activation. Whereas, the activation process of IKK, the functions of NEMO ubiquitination, IKK-related non-canonical pathway and the nuclear transportation of NEMO and functions of IKKα are still debated in cell death. In addition, cluster of differentiation 95 (CD95)-mediated non-apoptotic signaling and CD95- death-inducing signaling complex (DISC) interactions are waiting for clarification.