Abstract
A calmodulin-like protein, which is identical in size and 85% identical to vertebrate calmodulin, was recently identified by 'subtractive hybridization' comparison of transcripts expressed in normal versus transformed human mammary epithelial cells. Unlike the ubiquitous distribution of calmodulin, calmodulin-like protein expression is restricted to certain epithelial cells, and appears to be modulated during differentiation. In addition, calmodulin-like protein levels are often significantly reduced in malignant tumor cells as compared to corresponding normal epithelial cells. The current studies compare calmodulin-like protein functions with those of calmodulin. We find that calmodulin-like protein activation of multifunctional Ca2+/calmodulin-dependent protein kinase II (calmodulin kinase II) is equivalent to activation by calmodulin, but that four other calmodulin-dependent enzymes, cGMP phosphodiesterase, calcineurin, nitric-oxide synthase, and myosin-light-chain kinase, display much weaker activation by calmodulin-like protein than by calmodulin. In the case of myosin-light-chain kinase, calmodulin-like protein competitively inhibits calmodulin activation of the enzyme with a Ki value of 170 nM. Thus, calmodulin-like protein may have evolved to function as a specific agonist of certain calmodulin-dependent enzymes, and/or as a specific competitive antagonist of other calmodulin-dependent enzymes.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors
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3',5'-Cyclic-GMP Phosphodiesterases / metabolism
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Amino Acid Oxidoreductases / antagonists & inhibitors
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Amino Acid Oxidoreductases / metabolism
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Amino Acid Sequence
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Binding, Competitive
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Breast
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Calcineurin
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Calcium-Binding Proteins / chemistry
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Calcium-Binding Proteins / metabolism
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Calcium-Binding Proteins / pharmacology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calmodulin / chemistry
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Calmodulin / metabolism
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Calmodulin / pharmacology*
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Calmodulin-Binding Proteins / antagonists & inhibitors
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Calmodulin-Binding Proteins / metabolism
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Cells, Cultured
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Chromatography, Affinity
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Enzyme Activation / drug effects*
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Enzyme Inhibitors*
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Epithelium / chemistry
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Female
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Humans
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Molecular Sequence Data
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Myosin-Light-Chain Kinase / antagonists & inhibitors
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Myosin-Light-Chain Kinase / metabolism
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Nitric Oxide Synthase
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
Substances
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Calcium-Binding Proteins
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Calmodulin
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Calmodulin-Binding Proteins
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Enzyme Inhibitors
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Nitric Oxide Synthase
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Amino Acid Oxidoreductases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Myosin-Light-Chain Kinase
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Calcineurin
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Phosphoprotein Phosphatases
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3',5'-Cyclic-GMP Phosphodiesterases