DAPK1

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Death-associated protein kinase 1 (EC 2.7.11.1) (DAP kinase 1) [DAPK]

Publications[править]

SerThr-PhosphoProteome of Brain from Aged PINK1-KO A53T-SNCA Mice Reveals pT1928-MAP1B and pS3781-ANK2 Deficits, as Hub between Autophagy and Synapse Changes.

Hereditary Parkinson's disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCA in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As an exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension, and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was also detected for other microtubule and microfilament factors, namely MAP2 , MARK1 , MAP1A , KIF1A , 4.1N , 4.1G , and ADD2 . While the MAP1B heavy chain supports regeneration and growth cones, its light chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2 , VPS13D , and VPS13C in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in [i]Drosophila melanogaster[/i] that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, [i]ANK2[/i] gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.

MeSH Terms

  • Aging
  • Amino Acid Sequence
  • Animals
  • Ankyrins
  • Autophagy
  • Brain
  • Mice, Knockout
  • Mice, Mutant Strains
  • Microtubule-Associated Proteins
  • Microtubules
  • Phosphoproteins
  • Phosphorylation
  • Phosphoserine
  • Phosphothreonine
  • Protein Domains
  • Protein Kinases
  • Proteome
  • Synapses
  • alpha-Synuclein

Keywords

  • PINK1
  • Parkinson’s disease
  • alpha-synuclein
  • autophagy
  • brain phosphorylome
  • microtubular cytoskeleton
  • synaptic signaling


Degradation of Caytaxin Causes Learning and Memory Deficits via Activation of DAPK1 in Aging.

Loss of memory is an inevitable clinic sign in aging, but its underlying mechanisms remain unclear. Here we show that death-associated protein kinase (DAPK1) is involved in the decays of learning and memory in aging via degradation of Caytaxin, a brain-specific member of BNIP-2. DAPK1 becomes activated in the hippocampus of mice during aging. Activation of DAPK1 is closely associated with degradation of Caytaxin protein. Silencing Caytaxin by the expression of small interfering RNA (siRNA) that targets specifically to Caytaxin in the hippocampus of adult mice impairs the learning and memory. Genetic inactivation of DAPK1 by deletion of DAPK1 kinase domain prevents the degradation of Caytaxin and protects against learning and memory declines. Thus, activation of DAPK1 impairs learning and memory by degrading Caytaxin during aging.

MeSH Terms

  • Aging
  • Animals
  • Caspase 3
  • Death-Associated Protein Kinases
  • Enzyme Activation
  • Gene Silencing
  • Male
  • Memory
  • Memory Disorders
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins
  • Neurons
  • Proteolysis

Keywords

  • Aging
  • Caytaxin
  • DAPK1
  • Learning and memory


Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition.

The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status. We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR. Considering tumors with telomere shortening, expression for BNIP3, DAPK1, NDRG1, EGFR, and [[CDKN2A]] was significantly higher in NSCLC than in CRC, whereas TP53 was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, DAPK1, GADD45A, SHC1, and TP53 were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC. In NSCLC, the failure of pathways which involve factors such as DAPK1, GADD45A, SHC1, and TP53, in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis.

MeSH Terms

  • Adenocarcinoma
  • Aged
  • Aging
  • Biomarkers, Tumor
  • Carcinoma, Large Cell
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Squamous Cell
  • Cell Death
  • Colon
  • Colorectal Neoplasms
  • Female
  • Gene Expression Profiling
  • Humans
  • Lung
  • Lung Neoplasms
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Rectum
  • Telomerase
  • Telomere
  • Telomere Shortening