Cytoplasmic signalling by the c‐Abl tyrosine kinase in normal and cancer cells

Sirvent, Audrey; Bénistant, Christine; Roche, Serge

doi:10.1042/bc20080020

Cited by 135 publications

(143 citation statements)

References 107 publications

(206 reference statements)

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“…32 Furthermore, no amplifications of any of the other tyrosine kinases that were evaluated were observed. It is noteworthy that, in nonrhabdoid solid tumors, c-Abl is coexpressed commonly with tyrosine kinase receptors like PDGFR or epidermal growth factor receptor, 33 which does not appear to be the case in rhabdoid tumors. Nevertheless, the observed expression of c-Abl in rhabdoid tumors provides a rationale for novel treatment concepts, such as specific tyrosine kinase inhibitors like dasatinib and imatinib.…”

Section: Discussionmentioning

confidence: 98%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

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BACKGROUND: Atypical teratoid/rhaboid tumors (AT/RTs) and extracranial malignant rhabdoid tumors are highly malignant neoplasms with a dismal prognosis. These tumors predominantly affect infants and targeted, adjuvant treatment approaches would be highly desirable. METHODS: In the current study, the authors investigated the expression and functional role of tyrosine kinases in 2 malignant rhabdoid tumor cell lines (A204 and G401) and in a series of 5 AT/RTs and 18 malignant rhabdoid tumors (13 rhabdoid tumors of the kidney and 5 extrarenal rhabdoid tumors). RESULTS: Both cell lines consistently expressed the tyrosine kinase c-Abl, which promoted proliferation as assessed by small interfering RNA knockdown. Blockage of c-Abl using the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth in both cell lines. Furthermore, c-Abl was expressed in all rhabdoid tumors, whereas expression of platelet-derived growth factor receptor subtypes alpha and beta was infrequent and c-Kit expression was absent. CONCLUSIONS: The current data pointed toward a role for c-Abl in the biology of malignant rhabdoid tumors and provided a rationale for the investigation of tyrosine kinase inhibitors that target c-Abl for the treatment of these aggressive tumors. Cancer 2010;116:5075-81.

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Section: Discussionmentioning

confidence: 98%

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

Koos

Jeibmann

Lünenbürger

et al. 2010

Cancer

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“…However, it is possible that the Hippo pathway prevents proliferation through other mechanisms as well. Although this study focused on the apoptotic role of c-Abl, c-Abl is also a pro-proliferative factor (reviewed in Sirvent et al 48 and Colicelli 49 ). Activation of c-Abl in the cytoplasm is involved in the response to growth factors [50][51][52] and F-actin assembly.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

et al. 2013

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The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.

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“…5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. [6][7][8] Recently, Ko et al 9 and Imam et al 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates.…”

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confidence: 82%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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Cytoplasmic signalling by the c‐Abl tyrosine kinase in normal and cancer cells

Cited by 135 publications

References 107 publications

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

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