Abstract
Epidermal growth factor receptor (EGFR) initiates a signaling cascade that leads to DNA synthesis and cell proliferation, but its role in regulating DNA replication licensing is unclear. Here, we show that activated EGFR phosphorylates the p56 isoform of Lyn, p56(Lyn), at Y32, which then phosphorylates MCM7, a licensing factor critical for DNA replication, at Y600 to increase its association with other minichromosome maintenance complex proteins, thereby promoting DNA synthesis complex assembly and cell proliferation. Both p56(Lyn) Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cells and correlated with poor survival of breast cancer patients. These results establish a signaling cascade in which EGFR enhances MCM7 phosphorylation and DNA replication through Lyn phosphorylation in human cancer cells.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology*
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Cell Proliferation
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DNA Replication / physiology*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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ErbB Receptors / physiology*
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Female
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Humans
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Mice
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Minichromosome Maintenance Complex Component 7
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Phosphorylation
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Prognosis
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Signal Transduction
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Tyrosine / chemistry
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Tyrosine / metabolism
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src-Family Kinases / metabolism*
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src-Family Kinases / physiology
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Tyrosine
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ErbB Receptors
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lyn protein-tyrosine kinase
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src-Family Kinases
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MCM7 protein, human
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Minichromosome Maintenance Complex Component 7