Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells

Ewald, Jonathan A.; Wilkinson, John; Guyer, Cheryl A.; Staros, James V.

doi:10.1016/s0014-4827(02)00014-9

Cited by 38 publications

(45 citation statements)

References 58 publications

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“…36 Furthermore, recent studies have demonstrated that in fact, many kinases, not in the MAPK family, also have functions independent of their catalytic activities. 37,38 For instance, in addition to its role as a key cell cycle regulator, CDK1 in S. cerevisiae is shown also to have a kinase activity-independent function in regulation of gene expression. 39 The p38α MAPK is rapidly activated in response to many stress stimuli.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

Fan

Yang²,

Du³

et al. 2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2125 KEY WORDSp38α, cell cycle, checkpoint control, cancer, siRNA and kinase inhibitor ACKNOWLEDGEMENTSWe thank Dr. Richard Gaynor for his interest, support and valuable discussions. We thank Jack Dempsey for assistance in flow cytometry; Hui Yang and Danny Van Horn for assistance in microscopy. Report A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity ABSTRACTActivation of p38α MAPK triggers G 2 /M checkpoint, thus inhibiting cell proliferation. In this study we found that depletion of p38α by RNAi also inhibited cell proliferation and caused mitotic arrest. However, treatment with selective small molecule p38 kinase inhibitors had no effect on cell cycle progression, even though the p38 kinase was completely inhibited, revealing p38α functions that are independent of its kinase activity. Indeed, ectopic expression of a kinase negative p38α rescued the lethality caused by RNAi-depletion of the endogenous p38α, thus providing further evidence for a kinase-independent function of p38α. In addition, we showed that overexpression of the wild type or kinase-negative p38α also strongly inhibited cell proliferation, similarly as RNAi depletion of p38α. Together the results demonstrate that, in addition to its kinase-dependent functions, such as in activation of G 2 /M checkpoint, p38α also has an essential, kinase-independent function.

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Section: Discussionmentioning

confidence: 99%

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

Fan

Yang²,

Du³

et al. 2005

Cell Cycle

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“…Without ruling out the possibility that DYRK1A affects other signaling pathways in the GBM-TICs, our data show that the blockade inhibits EGFR stability, and therefore targeting EGFR for degradation could be more effective than inhibiting its kinase activity. In fact, a kinase-defective EGFR can stimulate DNA synthesis (47) and enhance cell survival (48). In this regard, it was proposed that one potential mode of action of the monoclonal antibodies directed against EGFR, which are currently undergoing phase III trials for glioma treatment, may involve their ability to target EGFR for lysosomal degradation (49).…”

Section: Primary Lines and Culture Conditionsmentioning

confidence: 99%

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

126

149

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Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo-and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumorinitiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

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“…The mutations are clinically relevant, as they are linked to tumor sensitivity to ATPcompetitive, small-molecule EGFR inhibitors, such as gefitinib and erlotinib. These are localized in exons 18,19,20, and 21 of the EGFR gene, which encode the kinase domain. Although a secondary mutation responsible for drug resistance has also been predicted (15) and reported (16), the molecular mechanism of signaling by drug-sensitive and drug-resistant EGFRs is not entirely defined.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, to minimize background signaling caused by other ErbB receptors and ligands, we developed a ''clean system'' with 32D mouse hematopoietic cells. These are interleukin-3 (IL-3)-dependent cells, which do not express any of the ErbB coreceptors or ligands and have been used previously to study EGFR signaling (17)(18)(19)(20)(21) as well as that of other oncogenic tyrosine kinases (22)(23)(24). Thus, we used 32D cells transfected with EGFR mutant vectors and human lung cancer cell lines harboring EGFR gene mutations in the activation loop.…”

Section: Introductionmentioning

confidence: 99%

Association with HSP90 Inhibits Cbl-Mediated Down-regulation of Mutant Epidermal Growth Factor Receptors

Yang

Perez-Tores

et al. 2006

Cancer Research

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Activating mutations in the epidermal growth factor receptor (EGFR), localized in the activation loop within the kinase domain, have been discovered in non-small cell lung cancers (NSCLC). Most of these mutants are exquisitely sensitive to EGFR tyrosine kinase inhibitors, suggesting that they generate receptor dependence in the cancers that express them. 32D cells stably expressing EGFR-L861Q and EGFR-L858R but not wild-type EGFR exhibited ligand-independent receptor phosphorylation and viability. Ligand-induced receptor downregulation (LIRD) was impaired in mutant-expressing cells. The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand. Inhibition of HSP90 activity with geldanamycin restored Cbl function as indicated by receptor ubiquitination and LIRD. These results suggest that EGFR mutants form defective endocytic complexes. In addition, HSP90 plays a role in maintaining the functional conformation of EGFR mutants and protecting activated

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Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells

Cited by 38 publications

References 58 publications

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Association with HSP90 Inhibits Cbl-Mediated Down-regulation of Mutant Epidermal Growth Factor Receptors

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Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells

Cited by 38 publications

References 58 publications

A Novel Role of p38&alpha; MAPK in Mitotic Progression Independent of Its Kinase Activity

A Novel Role of p38&alpha; MAPK in Mitotic Progression Independent of Its Kinase Activity

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Association with HSP90 Inhibits Cbl-Mediated Down-regulation of Mutant Epidermal Growth Factor Receptors

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A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity