Abstract
Laminin-5 and alpha3beta1 integrin promote keratinocyte survival; however, the downstream signaling pathways for laminin-5/alpha3beta1 integrin-mediated cell survival had not been fully established. We report the unexpected finding of multiple interactions between 14-3-3 isoforms and proapoptotic proteins in the survival signaling pathway. Ln5-P4 motif within human laminin-5 alpha3 chain promotes cell survival and anti-apoptosis by inactivating Bad and YAP. This effect is achieved through the formation of 14-3-3zeta/p-Bad and 14-3-3sigma/p-YAP complexes, which is initiated by alpha3beta1 integrin and FAK/PI3K/Akt signaling. These complexes result in cytoplasmic sequestration of Bad and YAP and their subsequent inactivation. An increase in Akt1 activity in cells induces 14-3-3zeta and sigma, p-Bad, and p-YAP, promoting cell survival, whereas decreasing Akt activity suppresses the same proteins and inhibits cell survival. Suppression of 14-3-3zeta with RNA-interference inhibits cell viability and promotes apoptosis. These results reveal a new mechanism of cell survival whereby the formation of 14-3-3zeta/p-Bad and 14-3-3sigma/p-YAP complexes is initiated by laminin-5 stimulation via the alpha3beta1 integrin and FAK/PI3K/Akt signaling pathways, thereby resulting in cell survival and anti-apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / agonists
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14-3-3 Proteins / genetics
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14-3-3 Proteins / metabolism*
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Amino Acid Motifs / physiology
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cell Adhesion Molecules / pharmacology
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Cell Cycle Proteins
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Child, Preschool
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Focal Adhesion Kinase 1 / drug effects
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Focal Adhesion Kinase 1 / metabolism
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Gene Knockdown Techniques
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Humans
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Infant
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Integrin alpha3beta1 / drug effects
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Integrin alpha3beta1 / metabolism*
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Kalinin
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Morpholines / pharmacology
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Nuclear Proteins / drug effects
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Protein Isoforms / agonists
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transcription Factors / drug effects
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Transcription Factors / metabolism
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Wound Healing*
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bcl-Associated Death Protein / drug effects
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bcl-Associated Death Protein / metabolism
Substances
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14-3-3 Proteins
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BAD protein, human
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Cell Adhesion Molecules
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Cell Cycle Proteins
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Chromones
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Enzyme Inhibitors
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Integrin alpha3beta1
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Morpholines
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Nuclear Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Isoforms
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RNA, Small Interfering
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Transcription Factors
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YY1AP1 protein, human
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bcl-Associated Death Protein
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Proto-Oncogene Proteins c-akt