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.