Abstract
We identified dynein light chain 1 (DLC1) as a physiologic substrate of p21-activated kinase 1 (Pak1). Pak1-DLC1 interaction plays an essential role in cell survival, which depends on Pak1's phosphorylation of DLC1 on Ser88. Pak1 associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein, and phosphorylates both proteins. Phosphorylation of BimL by Pak1 prevents it from interacting with and inactivation of Bcl-2, an antiapoptotic protein. Overexpression of DLC1 but not DLC1-Ser88Ala mutant promotes cancerous properties of breast cancer cells. DLC1 protein level is elevated in more than 90% of human breast tumors. The regulation of cell survival functions by Pak1-DLC1 interaction represents a novel mechanism by which a signaling kinase might regulate the cancerous phenotypes.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alanine / chemistry
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Apoptosis*
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Blotting, Western
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Breast Neoplasms / pathology
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Carrier Proteins / pharmacology*
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Cell Cycle
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Cell Division
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Cell Line, Tumor
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Cell Survival
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Cell Transformation, Neoplastic
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Drosophila Proteins*
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Dyneins
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Flow Cytometry
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Gene Expression Regulation, Neoplastic
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Glutathione Transferase / metabolism
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Humans
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Immunohistochemistry
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Microscopy, Fluorescence
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Mutation
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Neoplasms / pathology*
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Phenotype
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Phosphorylation
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Plasmids / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Serine / chemistry
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Signal Transduction
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Time Factors
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Two-Hybrid System Techniques
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Up-Regulation
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p21-Activated Kinases
Substances
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Carrier Proteins
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Drosophila Proteins
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Serine
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Glutathione Transferase
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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Dyneins
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Alanine