Abstract
Mammalian septins are GTP-binding proteins the functions of which are not well understood. Knockdown of SEPT2, 6, and 7 causes stress fibers to disintegrate and cells to lose polarity. We now show that this phenotype is induced by nuclear accumulation of the adaptor protein NCK, as the effects can be reversed or induced by cytoplasmic or nuclear NCK, respectively. NCK is carried into the nucleus by SOCS7 (suppressor of cytokine signaling 7), which possesses nuclear import/export signals. SOCS7 interacts with septins and NCK through distinct domains. DNA damage induces actin and septin rearrangement and rapid nuclear accumulation of NCK and SOCS7. Moreover, NCK expression is essential for cell-cycle arrest. The septin-SOCS7-NCK axis intersects with the canonical DNA damage cascade downstream of ATM/ATR and is essential for p53 Ser15 phosphorylation. These data illuminate an unanticipated connection between septins, SOCS7, NCK signaling, and the DNA damage response.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism*
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Cycle* / drug effects
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Cell Cycle* / radiation effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism*
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Cell Nucleus / radiation effects
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Cell Proliferation
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Cell Shape
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Cytoplasm / metabolism
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Cytoskeletal Proteins
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DNA Damage*
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DNA-Binding Proteins / metabolism
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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HeLa Cells
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Humans
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Hydroxyurea / pharmacology
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Mice
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Mice, Knockout
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Mitomycin / pharmacology
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Multiprotein Complexes / metabolism
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Mutagens / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Phenotype
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Septins
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Signal Transduction
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism*
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism
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Ultraviolet Rays
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Multiprotein Complexes
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Mutagens
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NCK2 protein, human
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Nck protein
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Nuclear Proteins
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Oncogene Proteins
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RNA, Small Interfering
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SOCS7 protein, human
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Suppressor of Cytokine Signaling Proteins
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TP53 protein, human
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Mitomycin
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Phosphoric Monoester Hydrolases
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GTP-Binding Proteins
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SEPTIN6 protein, human
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SEPTIN7 protein, human
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Septins
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Hydroxyurea