Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto, Yasunori; Morii, Mariko; Miura, Takahito; Kubota, Sho; Ishibashi, Keiichiro; Honda, Takeshi; Okamoto, Aya; Yamaguchi, Noritaka; Iwama, Atsushi; Nakayama, Yuji; Yamaguchi, Naoto

doi:10.1074/jbc.m113.533752

Cited by 34 publications

(36 citation statements)

References 96 publications

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“…SU6656 decreased autophosphorylation of SFKs [Active Src (pY416)] 3 h after SU6656 addition ( Figure 2F). We also examined the effect of SU6656 in the nuclear fraction, as our previous work suggested that SFKs suppress ATR-Chk1 signaling in the nucleus (Fukumoto et al, 2014a). Subcellular fractionation showed that SU6656 also decreased the autophosphorylation of SFKs in the nucleus ( Figure 2G).…”

Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 90%

“…Actin, Chk1, Chk1-pS317, Chk1-pS345, cPLA2, Desmoglein, g-H2AX, Hsc70, Lyn, and c-Yes antibodies were obtained as described previously (Takahashi et al, 2009;Fukumoto et al, 2014a). MoBU-1, Merck Millipore, NA61), Chk2 (cl.…”

Section: Antibodiesmentioning

confidence: 99%

“…Recently, we showed that SFKs inhibit ATR-Chk1 signaling to promote recovery from the G2 DNA damage checkpoint after Adriamycin exposure (Fukumoto et al, 2014a). However, the role of SFKs in the recovery from other checkpoints is unclear.…”

Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 99%

“…We showed that shRNA targeting Lyn (shLyn), but not Fyn (shFyn), or c-Yes (shYes), increases thymidineinduced Rad17 phosphorylation by ATR (Fukumoto et al, 2014a). However, in spite of the fact that Rad17 phosphorylation is essential for ATR-dependent Chk1 phosphorylation (Bao et al, 2001), the effect of shLyn on Chk1 phosphorylation was marginal during the activation of replication checkpoint (Fukumoto et al, 2014a), and it is still unclear whether Lyn actually regulates the effector kinase Chk1 and the replication checkpoint. Therefore, we examined the effect of shLyn on Chk1 phosphorylation during the recovery from the replication checkpoint.…”

Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 99%

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Src family kinases maintain the balance between replication stress and the replication checkpoint

Miura

Fukumoto

Morii

et al. 2015

Cell Biology International

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Progression of DNA replication is tightly controlled by replication checkpoints to ensure the accurate and rapid duplication of genetic information. Upon replication stress, the replication checkpoint slows global DNA replication by inhibiting the late-firing origins and by slowing replication fork progression. Activation of the replication checkpoint has been studied in depth; however, little is known about the termination of the replication checkpoint. Here, we show that Src family kinases promote the recovery from replication checkpoints. shRNA knockdown of a Src family kinase, Lyn, and acute chemical inhibition of Src kinases prevented inactivation of Chk1 after removal of replication stress. Consistently, Src inhibition slowed resumption of DNA replication, after the removal of replication blocks. The effect of Src inhibition was not observed in the presence of an ATM/ATR inhibitor caffeine. These data indicate that Src kinases promote the resumption of DNA replication by suppressing ATR-dependent replication checkpoints. Surprisingly, the resumption of replication was delayed by caffeine. In addition, Src inhibition delayed recovery from replication fork collapse. We propose that Src kinases maintain the balance between replication stress and the activity of the replication checkpoint.

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Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 90%

Section: Antibodiesmentioning

confidence: 99%

Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 99%

Section: Lyn Suppresses Atr-chk1 Signaling During Recovery From the Rmentioning

confidence: 99%

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Src family kinases maintain the balance between replication stress and the replication checkpoint

Miura

Fukumoto

Morii

et al. 2015

Cell Biology International

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“…Immunodetection was performed as reported previously (10,26). Results were analyzed using an image analyzer ChemiDoc XRSplus (Bio-Rad).…”

mentioning

confidence: 99%

Activation of Lyn Tyrosine Kinase through Decreased Membrane Cholesterol Levels during a Change in Its Membrane Distribution upon Cell Detachment

Morinaga

Abe

Nakayama

et al. 2014

Journal of Biological Chemistry

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Background: Lyn tyrosine kinase is anchored to the plasma membrane. Results: Cell detachment changes Lyn distribution from the low density to the high density membrane fractions and activates Lyn through decreased membrane cholesterol levels. Conclusion: Cell detachment-induced Lyn activation plays a role in survival of suspension cells. Significance: Our results provide novel insight into signal transduction upon cell detachment.

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c‐Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity‐dependent manner

Aoyama

Yamaguchi

Yuki

et al. 2015

Cell Biology International

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c-Abl is a non-receptor-type tyrosine kinase that regulates various cellular events, including cell proliferation, differentiation, and apoptosis, through phosphorylation of cytoplasmic and nuclear targets. Although we showed that c-Abl induces histone deacetylation, the molecular mechanisms of this phenomenon are largely unknown. Here, we analyzed the effect of c-Abl on the expression of histone deacetylase 1 (HDAC1), because c-Abl was shown to be involved in maintenance of nuclear protein levels of HDAC1. Co-transfection of HDAC1 with c-Abl increased the levels of HDAC1 protein in a kinase activity-dependent manner without affecting its mRNA levels. Treatment with the proteasome inhibitor MG132 increased protein levels of HDAC1 in cells transfected with HDAC1 but not in cells co-transfected with HDAC1 and c-Abl. Among class I HDACs, knockdown of endogenous c-Abl preferentially suppressed endogenous protein levels of HDAC1, suggesting that c-Abl stabilizes HDAC1 protein by inhibiting its proteasomal degradation. Subcellular fractionation showed that the stabilization of HDAC1 by c-Abl occurred in the nucleus. Despite the fact that HDAC1 was phosphorylated by co-expression with c-Abl, stabilization of HDAC1 by c-Abl was not affected by mutations in its sites phosphorylated by c-Abl. Co-expression with HDAC1 and nuclear-targeted c-Abl did not affect HDAC1 stabilization. Therefore, these results suggest that c-Abl induces HDAC1 stabilization possibly through phosphorylation of a cytoplasmic target that is involved in proteasomal degradation of HDAC1.

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Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Cited by 34 publications

References 96 publications

Src family kinases maintain the balance between replication stress and the replication checkpoint

Src family kinases maintain the balance between replication stress and the replication checkpoint

Activation of Lyn Tyrosine Kinase through Decreased Membrane Cholesterol Levels during a Change in Its Membrane Distribution upon Cell Detachment

c‐Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity‐dependent manner

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