c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy

Moya, Eva M; Hernández-Losa, Javier; Luquero, Clara I. Aceves; Cruz-Morcillo, Miguel A. de la; Ramírez-Castillejo, Carmen; Callejas‐Valera, Juan Luis; Arriaga, Á.; Aranburo, Antonio Fernandez; Cajal, Santiago Ramón y; Gutkind, J. Silvio; Sánchez‐Prieto, Ricardo

doi:10.1002/ijc.23063

Cited by 33 publications

(26 citation statements)

References 35 publications

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“…However, a kinase-deficient mutant form of Abl retained partial activity in promoting myogenesis and stimulating p38 MAPK activity in transfectants. This is consistent with two previous reports in which Abl overexpressed in 293 cells activated p38 and Abl-KD retained partial (10), or nearly full (15), ability to do so. We speculate that, in addition to acting as a kinase in Cdo-containing complexes, Abl may play a role as a scaffolding factor, bridging Cdo and JLP, and helping to assemble or stabilize other components of the complex that are involved in p38 activation.…”

Section: Discussionsupporting

confidence: 93%

“…These results suggest that Abl may possess both kinase-dependent and -independent functions during myogenic differentiation. Although most known Abl functions are dependent on kinase activity, there is precedent for Abl-KD possessing the ability to promote p38 MAPK activity (10,15), which is linked to Cdo's and Abl's promyogenic function (reference 42 and see below, respectively).…”

Section: Resultsmentioning

confidence: 99%

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Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

Bae

Kim

Lee

et al. 2009

Molecular and Cellular Biology

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The p38 mitogen-activated protein kinase (MAPK) pathway is required for differentiation of skeletal myoblasts, but how the pathway is activated during this process is not well understood. One mechanism involves the cell surface receptor Cdo (also known as Cdon), which binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38, respectively; formation of these complexes results in Bnip-2/Cdc42-dependent activation of p38. It has been reported that the tyrosine kinase Abl promotes myogenic differentiation in a manner dependent on its cytoplasmic localization, but the cytoplasmic signaling proteins with which it interacts to achieve this effect are unidentified. We report that Abl associates with both Cdo and JLP during myoblast differentiation. Abl binds a proline-rich motif in Cdo via its SH3 domain, and these regions of Abl and Cdo are required for their promyogenic effects. Cdo is important for full Abl kinase activity, and Abl is necessary for full activation of p38 MAPK, during myogenic differentiation. As seen with myoblasts depleted of Cdo, the diminished differentiation displayed by Abl-depleted cells is rescued by the expression of an activated form of the immediate upstream p38-activating kinase MAPK kinase 6. Abl's promyogenic effect is therefore linked to a multiprotein cell surface complex that regulates differentiation-dependent p38 activation.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

Bae

Kim

Lee

et al. 2009

Molecular and Cellular Biology

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“…Thus, the p38MAPK signaling pathway has been shown to be a major mediator in the response and resistance to several antitumor agents such as cisplatin, ara-c or gemcitabine (Losa et al, 2003;Habiro et al, 2004;Koizumi et al, 2005;Sanchez-Arevalo et al, 2005;Galan-Moya et al, 2008). Interestingly, ara-c and gemcitabine are members of the same family of 5-FU (anti-metabolites), but no relationship between 5-FU resistance and p38MAPK has been reported.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

et al. 2011

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5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKa by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.

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“…133 Conversely, transfection of a constitutively active form of c-Abl into tumorigenic 4T1 cells promoted a epithelial-like morphology and inhibited tumor growth, whereas low concentrations of imatinib had no effect on 4T1 tumor growth. 133 Moreover, expression of a kinase-inactive form of c-Abl (which might not act as a dominant-negative since c-Abl has kinase-independent functions) [134][135][136] promoted invasion toward TGF-β, whereas expression of a constitutively active form prevented TGF-β-induced invasion, MMP expression, and proliferation. 133 These results contrast with data in human cancer cells demonstrating that inhibition/silencing of c-Abl and/or Arg inhibits matrix degradation, MMP activation, invasion, and PDGFinduced EMT.…”

Section: 8498mentioning

confidence: 99%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

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c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy

Cited by 33 publications

References 35 publications

Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

Cdo Binds Abl To Promote p38α/β Mitogen-Activated Protein Kinase Activity and Myogenic Differentiation

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

Activation of Abl Family Kinases in Solid Tumors

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