DAPK1’s role in apoptosis and the related molecular regulations of cancer pathways and neuronal damage
DAPK1 is among the proteins positively regulating cell death by apoptosis and thus working to prevent cancer metastases. We have already seen that glyphosate suppresses melatonin synthesis, and that melatonin plays a critical role in suppressing DAPK1 activity [39,87]. DAPK1 is a potent modulator of PIN1 activity and their molecular interactions are significantly implicated in the development of tau-associated pathology [104], in the amyloid β-related pathology of Alzheimer’s disease (AD) [152] and in the disablement of neuronal network restoration following neural traumas [153]. Therefore, as DAPK1 directly inhibits PIN1 function [86], it is important to revisit DAPK1 regulatory aspects of activation and/or deactivation that relate to the DAPK1 tertiary structure. These regulatory activities affect the molecular activity of PIN1 and other important molecules implicated in neurodegeneration and cancer.
DAPK1 has a multi-domain structural organization that enables it to perform a wide range of functions, succinctly described in a study by P Singh et al. [86]. What is outstanding about this molecule, and a feature that differentiates it from other kinases, is that DAPK1 does not require an extra phosphorylation event in its catalytic domain to become activated. Near the DAPK1 catalytic kinase domain, there is an autoregulatory Ca2+/CaM domain that serves as a pseudo-substrate for the catalytic domain, and when CaM is not bound to that region, the function of DAPK1 is auto-inhibited. It is for this reason that the catalytic domain of DAPK1 is unique compared to other kinases.
Adjacent to the peptide-to-peptide region in the catalytic domain, there is a protruding positively charged comb region that allows for numerous regulatory properties of DAPK1, including the regulation of apoptosis [154]. However, it is the extra-catalytic domain molecular interactions that are important for DAPK1’s activity, degradation and cellular localization. Next to the CaM autoregulatory domain (which inhibits the catalytic domain of DAPK1 in the absence of CaM), lies an ankyrin repeat rich domain, which is responsible for many of the protein’s interactions. This ankyrin repeat rich domain determines DAPK1’s ubiquitination status and subsequent proteasomal degradation.
DAPK1, Anoikis and Synapses: In the absence of the ankyrin repeats, DAPK1 localizes from actin filaments to focal adhesions, and this relates to tropomyosin regulation by DAPK1 phosphorylation and facilitation of cancer cell death. This function of DAPK1 is very important as it regulates the phenomenon called anoikis that prevents cancer. Anoikis is a distinct cell-death process similar to apoptosis, and it reflects the capacity that normal cells have to migrate and stay alive; whereas, when DAPK1 is activated in cancer cells that attach to soft surfaces, anoikis is initiated and these cells die, thus restricting their migration and metastatic potential [155,156]. Anoikis is a safeguard mechanism that lets healthy cells remain alive and functional, whereas it kills abnormal neural cells that have pathological adherence junctions during embryonic development.
DAPK1’s ankyrin repeat sequence is essential for its protein-to-protein communication, as is the case for many other ankyrin repeat proteins [157]. For DAPK1, the ankyrin repeat domain mainly functions to provide control of its amounts in cells, regulated via ubiquitination and proteasomal degradation of the protein [158]. The DAPK1 ankyrin repeats react strongly with DAPK interacting protein-1 (DIP-1), targeting the proteasomal degradation of DAPK1. Thus, whether or not DAPK1 will exert apoptosis survival signaling in normal cells depends on the expression and interactions of its ankyrin repeat domain with DIP-1. When DIP-1 is expressed, it forms a strong complex with DAPK1 and DAPK1 suffers from DIP-1’s ubiquitination in the complex and it is thereby tagged for proteasomal degradation [158]. However, when the DAPK1 ankyrin repeat domain is deleted, DAPK1 relocalizes from actin cytoskeleton microfilaments to adhesion complexes where it exerts cell death by anoikis of migrating cancer cells [156].
DAPK1 is strongly involved in neuronal cell death and the development of neurodegeneration [159]. Furthermore, anoikis is considered as a key pathogenic factor for glaucoma, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) [160,161]. Therefore, whether the anoikis mechanism of cell death will appear in a certain type of cell ultimately depends on the functionality of the ankyrin repeat domain of DAPK1.
Although research on the relationship between anoikis and prion disease is sparse, there is growing evidence for a role for anoikis in prion disease pathogenesis. The prion protein modulates epithelial to mesenchymal cell transition [162], and anoikis crosstalk with epithelial-mesenchymal transition in resisting cancer metastasis is substantial [163]. Moreover, the prion protein is upregulated in many cancers [164]. Therefore, a potential DAPK1 upregulation and re-localization from microfilaments to adhesion complexes may underly both neurodegenerative and prion disease pathology.
Figure 1 provides a graphical representation of these complex processes relating disturbed expression of PIN1 and DAPK1 to disease.