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Title: Regulation of hERG and hEAG channels by Src and by SHP-1 tyrosine phosphatase via an ITIM region in the cyclic nucleotide binding domain
Authors: Schlichter L.C.
Jiang J.
Wang J.
Newell E.W. 
Tsui F.W.L.
Lam D.
Keywords: cyclic nucleotide
potassium channel
potassium channel hEAG
potassium channel HERG
protein tyrosine kinase
protein tyrosine phosphatase SHP 1
unclassified drug
amino acid sequence
controlled study
enzyme activation
enzyme activity
human cell
immunoreceptor tyrosine based inhibition motif
nucleotide binding site
nucleotide sequence
potassium current
protein phosphorylation
regulatory mechanism
Action Potentials
Amino Acid Sequence
Conserved Sequence
Cyclic AMP
Ether-A-Go-Go Potassium Channels
Gene Expression Regulation
HEK293 Cells
Molecular Sequence Data
Patch-Clamp Techniques
Protein Binding
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Sequence Homology, Amino Acid
Signal Transduction
src-Family Kinases
Issue Date: 2014
Publisher: Public Library of Science
Citation: Schlichter L.C., Jiang J., Wang J., Newell E.W., Tsui F.W.L., Lam D. (2014). Regulation of hERG and hEAG channels by Src and by SHP-1 tyrosine phosphatase via an ITIM region in the cyclic nucleotide binding domain. PLoS ONE 9 (2) : e90024. ScholarBank@NUS Repository.
Abstract: Members of the EAG K+ channel superfamily (ERG/Kv11.x, ELK/Kv12.x subfamilies) are expressed in many cells and tissues. In particular, two prototypes, EAG1/Kv10.1/KCNH1 and ERG1/Kv11.1/KCNH2 contribute to both normal and pathological functions. Proliferation of numerous cancer cells depends on hEAG1, and in some cases, hERG. hERG is best known for contributing to the cardiac action potential, and for numerous channel mutations that underlie 'long-QT syndrome'. Many cells, particularly cancer cells, express Src-family tyrosine kinases and SHP tyrosine phosphatases; and an imbalance in tyrosine phosphorylation can lead to malignancies, autoimmune diseases, and inflammatory disorders. Ion channel contributions to cell functions are governed, to a large degree, by post-translational modulation, especially phosphorylation. However, almost nothing is known about roles of specific tyrosine kinases and phosphatases in regulating K+ channels in the EAG superfamily. First, we show that tyrosine kinase inhibitor, PP1, and the selective Src inhibitory peptide, Src40-58, reduce the hERG current amplitude, without altering its voltage dependence or kinetics. PP1 similarly reduces the hEAG1 current. Surprisingly, an 'immuno-receptor tyrosine inhibitory motif' (ITIM) is present within the cyclic nucleotide binding domain of all EAG-superfamily members, and is conserved in the human, rat and mouse sequences. When tyrosine phosphorylated, this ITIM directly bound to and activated SHP-1 tyrosine phosphatase (PTP-1C/PTPN6/HCP); the first report that a portion of an ion channel is a binding site and activator of a tyrosine phosphatase. Both hERG and hEAG1 currents were decreased by applying active recombinant SHP-1, and increased by the inhibitory substrate-trapping SHP-1 mutant. Thus, hERG and hEAG1 currents are regulated by activated SHP-1, in a manner opposite to their regulation by Src. Given the widespread distribution of these channels, Src and SHP-1, this work has broad implications in cell signaling that controls survival, proliferation, differentiation, and other ERG1 and EAG1 functions in many cell types. © 2014 Schlichter et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0090024
Appears in Collections:Staff Publications

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