Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both clinical and experimental evidence illustrate that p190 and p210 BCR/ABL oncogenic tyrosine kinases induce resistance to DNA damage and confer an intrinsic genetic instability. Here, we investigated whether BCR/ABL expression could modulate nucleotide excision repair (NER). We found that ectopic expression of p210 BCR/ABL in murine lymphoid BaF3 cell line inhibited NER activity in vitro, promoting hypersensitivity of these cells to ultraviolet (UV) treatment and facilitating a mutator phenotype. However, expression of p210 BCR/ABL in human and murine myeloid cell lines and primary bone marrow cells resulted in the increased NER activity and resistance to UV irradiation. The ABL tyrosine kinase inhibitor STI571 reversed these effects, showing that p210 BCR/ABL tyrosine kinase activity is responsible for deregulation of NER. Hypoactivity of NER in p210 BCR/ABL-positive lymphoid cells was accompanied by the decreased interaction between proliferating cell nuclear antigen (PCNA) and xeroderma pigmentosum group B (XPB); conversely, this interaction was enhanced in p210 BCR/ABL-positive myeloid cells. p190 BCR/ABL did not affect NER in lymphoid and myeloid cells. In summary, our study suggests that p210 BCR/ABL reduced NER activity in lymphoid cells, leading to hypersensitivity to UV and mutagenesis. In contrast, p210 BCR/ABL expression in myeloid cells facilitated NER and induced resistance to UV.
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PMID:p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation. 1282 1

Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.
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PMID:Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology. 2651 33