Alpha kinase family, this different family includes eEF2K (eukaryotic elongation factor 2 kinase) in most eukaryotes, as well as many other kinases in various phyla.

eEF2K is an atypical "alpha kinase"

Eukaryotic elongation factor 2 kinase (eEF2K) is one of the few atypical "a kinase" members. It phosphorylates and inhibits eukaryotic elongation factor 2, thereby slowing the elongation phase of protein synthesis, which usually consumes a lot of energy and amino acids. eEF2K activity usually depends on calcium and calmodulin. eEF2K is also regulated by a number of other input signals, including by suppressing signals downstream of the anabolic signaling pathway, such as mammalian targets of rapamycin complex 1. The latest data show that eEF2K helps protect cancer cells from nutritional starvation and also has cytoprotective effects in other cases, including hypoxia. Increasing evidence indicates the role of eEF2K in neurological processes (such as learning and memory) and depression.

Regulation of eEF2K

In addition to being dependent on Ca²⁺/CaM, eEF2K activity is also regulated by phosphorylation, which occurs at several sites downstream of various signaling pathways. eEF2K activity is negatively regulated by mammalian rapamycin target 1 signaling. This protein kinase complex is activated by hormones, growth factors and amino acids and positively regulates mRNA translation and ribosome biogenesis. To date, three inputs have been identified from the mTORC1 signal to the eEF2K. Ser366 is phosphorylated by S6 kinase, which is phosphorylated and activated by mTORC1. Phosphorylation at this site renders eEF2K insensitive to Ca²⁺/CaM activation. mTORC1 also promotes phosphorylation of Ser359, and modification of this site strongly inhibits eEF2K. The nature of the proximal kinase is not fully understood – Cdc2/cyclin B can phosphorylate Ser359 and appears to be controlled by amino acids through mTORC1, but since insulin is not activated, it is unlikely to mediate its phosphorylation through, for example, insulin. This kinase. Ser78 immediately following the CaM binding motif is also phosphorylated in response to activation of the mTORC1 signal, although the proximal kinase is unknown. Phosphorylation here strongly weakens the interaction of eEF2K with CaM, thereby weakening its activation. Therefore, mTORC1 inhibits eEF2K through several phosphorylation sites, thereby promoting translation extension. This synergizes with the ability of this pathway to promote translation initiation. When amino acid and anabolic/proliferative stimulation determine EEF2K activation, it can stimulate protein synthesis.

Does eEF2K regulate autophagy?

Data provided by several studies suggest that silencing eEF2K or inhibiting its activity can impair autophagy induction under a variety of conditions, including treating glioma cells or depriving them of nutrition with 2-DOG or Akt inhibitor MK-2206. It has also been reported that eEF2K may mediate the induction of autophagy of mouse embryonic fibroblasts and the autophagy of breast cancer (MCF-7) cells in response to amino acid starvation or endoplasmic reticulum stress under conditions of nutrient deficiency or growth factor inhibition. Receptor tyrosine kinase eEF2K's role in promoting autophagy is attractive.

ChaK subfamily

TRPM7 is a typical representative of ChaK subfamily. TRPM7 (Transient Receptor Potential melastatin 7) is a transmembrane protein with dual functions of cation channels and kinase activity. As a non-selective cation channel, it can mediate inflow of divalent cations such as Mg²⁺, Ca²⁺, Zn²⁺ and outflow of monovalent cations such as K⁺ after opening; as a silk / threonine kinase, it can phosphorylate substrates and itself And can play the role of epigenetic factors, participate in gene expression regulation and other processes. TRPM7 is expressed in all tissues of the body, and is involved in intracellular Mg²⁺ homeostasis, cell migration, and adhesion. The unique structure, wide range of functions, and abundant expression make TRPM7 a promising new target for the treatment of major diseases such as cerebral ischemia, cardiovascular disease, and cancer.

Figure 1. Protein structure of TRPM7.

Reference

1. Kenney J W; et al. Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles. Advances in Biological Regulation, 2014, 55:15-27.