Browsing by Author "Hong, Yi-Ren"

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PhosphoPOINT: a comprehensive human kinase interactome and phospho-protein database
(2008-08-15)
Yang, Chia-Ying
;
Chang, Chao-Hui
;
Yu, Ya-Ling
;
Lin, Tsu-Chun Emma
;
Lee, Sheng-An
Motivation: To fully understand how a protein kinase regulates biological processes, it is imperative to first identify its substrate(s) and interacting protein(s). However, of the 518 known human serine/threonine/tyrosine kinases, 35 of these have known substrates, while 14 of the kinases have identified substrate recognition motifs. In contrast, 85 of the kinases have protein-protein interaction (PPI) datasets, raising the possibility that we might reveal potential kinase-substrate pairs from these PPIs. Results: PhosphoPOINT, a comprehensive human kinase interactome and phospho-protein database, is a collection of 4195 phospho-proteins with a total of 15 738 phosphorylation sites. PhosphoPOINT annotates the interactions among kinases, with their down-stream substrates and with interacting (phospho)-proteins to modulate the kinase-substrate pairs. PhosphoPOINT implements various gene expression profiles and Gene Ontology cellular component information to evaluate each kinase and their interacting (phospho)-proteins/substrates. Integration of cSNPs that cause amino acids change with the proteins with the phosphoprotein dataset reveals that 64 phosphorylation sites result in a disease phenotypes when changed; the linked phenotypes include schizophrenia and hypertension. PhosphoPOINT also provides a search function for all phospho-peptides using about 300 known kinase/phosphatase substrate/binding motifs. Altogether, PhosphoPOINT provides robust annotation for kinases, their downstream substrates and their interaction (phospho)-proteins and this should accelerate the functional characterization of kinomemediated signaling.
Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia
(2016-12-14)
Weng, Ching-Hui
;
Chung, Fa-Po
;
Chen, Yao-Chang
;
Lin, Shien-Fong
;
Huang, Po-Hsun
Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage.