Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530

Morii, Mariko; Kubota, Sho; Honda, Takeshi; Yuki, Ryuzaburo; Morinaga, Takao; Kuga, Tetsurō; Tomonaga, Takeshi; Yamaguchi, Noritaka; Yamaguchi, Naoto

doi:10.1074/jbc.m116.753202

Cited by 16 publications

(17 citation statements)

References 89 publications

(133 reference statements)

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“…Besides, Src can phosphorylate caspase-8 at tyrosin 397 to suppress apoptosis ( Tsang et al, 2016 ). Src may also inhibit apoptosis via directly phosphorylation at tyrosin 530 of Ku-70, which is a crucial protein to repair DNA double-strand breaks ( Morii et al, 2017 ). These results suggest Src could activate several pathways to cause chemoresistance in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Tzeng

Liu

et al. 2018

Front. Pharmacol.

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Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood.Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients.Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients.Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.

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Section: Discussionmentioning

confidence: 99%

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Tzeng

Liu

et al. 2018

Front. Pharmacol.

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“…Although Src substrates have been extensively hunted so far 5 , 6 , 28 , we showed that Src-family members are localized to the nucleus besides the plasma membrane 29 – 31 and revealed novel roles for Src-mediated tyrosine phosphorylation of chromosome-associated proteins 32 – 34 . Given that chromosome abnormalities happen until 24 h after v-Src induction (Figs 4 , 6 , 7 ), we hypothesize that some chromosome-associated proteins that are normally away from tyrosine phosphorylation may be aberrantly phosphorylated by v-Src in this period.…”

Section: Discussionmentioning

confidence: 87%

“…Cell lysates were prepared in SDS-sample buffer were separated by SDS-PAGE and electrotransferred onto polyvinylidene difluoride membranes (PVDF, Millipore). Immunodetection was performed as reported previously 20 , 34 , 36 , 43 . Sequential reprobing of membranes with a variety of antibodies was performed after the complete removal of primary and secondary antibodies from membranes in stripping buffer or inactivation of horseradish peroxidase by 0.1% NaN 3 , according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling

Honda

Morii

Nakayama

et al. 2018

Sci Rep

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v-Src is the first identified oncogene product and has a strong tyrosine kinase activity. Much of the literature indicates that v-Src expression induces anchorage-independent and infinite cell proliferation through continuous stimulation of growth signaling by v-Src activity. Although all of v-Src-expressing cells are supposed to form transformed colonies, low frequencies of v-Src-induced colony formation have been observed so far. Using cells that exhibit high expression efficiencies of inducible v-Src, we show that v-Src expression causes cell-cycle arrest through p21 up-regulation despite ERK activation. v-Src expression also induces chromosome abnormalities and unexpected suppression of v-Src expression, leading to p21 down-regulation and ERK inactivation. Importantly, among v-Src-suppressed cells, only a limited number of cells gain the ability to re-proliferate and form transformed colonies. Our findings provide the first evidence that v-Src-driven transformation is attributed to chromosome abnormalities, but not continuous stimulation of growth signaling, possibly through stochastic genetic alterations.

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“…1 a). Even though a number of anti-Fyn antibody reagents were commercially available to us, it was not possible to visualize endogenous centrosomal Fyn in HeLa cells despite their proper protein expression of Fyn 19 , 28 . To investigate the centrosomal localization of endogenous c-Src, we used Caco-2 cells, which strongly express c-Src, and found that c-Src also accumulated in the centrosome region (Fig.…”

Section: Resultsmentioning

confidence: 99%

Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

Morii

Kubota

Hasegawa

et al. 2021

Sci Rep

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Src-family tyrosine kinases (SFKs) play important roles in a number of signal transduction events during mitosis, such as spindle formation. A relationship has been reported between SFKs and the mitotic spindle; however, the underlying mechanisms remain unclear. We herein demonstrated that SFKs accumulated in the centrosome region at the onset of mitosis. Centrosomal Fyn increased in the G2 phase in a microtubule polymerization-dependent manner. A mass spectrometry analysis using mitotic spindle preparations was performed to identify tyrosine-phosphorylated substrates. Protein regulator of cytokinesis 1 (PRC1) and kinastrin/small kinetochore-associated protein (kinastrin/SKAP) were identified as SFK substrates. SFKs mainly phosphorylated PRC1 at Tyr-464 and kinastrin at Tyr-87. Although wild-type PRC1 is associated with microtubules, phosphomimetic PRC1 impaired the ability to bind microtubules. Phosphomimetic kinastrin at Tyr-87 also impaired binding with microtubules. Collectively, these results suggest that tyrosine phosphorylation of PRC1 and kinastrin plays a role in their delocalization from microtubules during mitosis.

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Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530

Cited by 16 publications

References 89 publications

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling

Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

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