EGFR Tyrosine 845 Phosphorylation-Dependent Proliferation and Transformation of Breast Cancer Cells Require Activation of p38 MAPK

Mueller, Kelly; Powell, Katelyn; Madden, Julie; Eblen, Scott T.; Boerner, Julie L.

doi:10.1593/tlo.12163

Cited by 41 publications

(34 citation statements)

References 27 publications

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“…This may be the consequence of ErbB1-Y845 phosphorylation induced by trastuzumab since it has been reported that ErbB1-Y845 phosphorylation is associated with ERK activity. 31 Increased ErbB1-Y845 phosphorylation was confirmed in SKBR3 cells following trastuzumab treatment (Fig. 1C), consistent with data shown in Figure 1A.…”

Section: Trastuzumab-induced Erbb2-y1248 Phosphorylation Correlates Wsupporting

confidence: 89%

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

Dokmanovic

Shen

et al. 2014

Cancer Biology & Therapy

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The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers.

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Section: Trastuzumab-induced Erbb2-y1248 Phosphorylation Correlates Wsupporting

confidence: 89%

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

Dokmanovic

Shen

et al. 2014

Cancer Biology & Therapy

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“…Phosphorylation of the EGFR, at Tyr845 can be stimulated by Src and b1 integrin activity at sites of ECM attachment, possibly through the binding of a Src-EGFR complex to b1 integrin to promote Src activation at the plasma membrane. Phosphorylation of the EGFR on Tyr845 can lead to phosphorylation of p38MAPK and the downstream target Gab1 (Mueller et al, 2012). Taken together with the recent study by Rajadurai and colleagues (Rajadurai et al, 2012) that shows that Gab1 directly interacts with cortactin to promote F-actin core formation, it is possible that integrin-induced activation of Src results in Src-mediated phosphorylation of the EGFR and cortactin to regulate the Gab1-cortactin interaction and subsequent F-actin remodeling during invadopodia formation.…”

Section: Discussionmentioning

confidence: 70%

“…Invadopodia formation has been shown to involve signaling through growth factor receptors, including the EGFR (Mader et al, 2011), which is a known target for Srcmediated phosphorylation. Src-mediated phosphorylation of the EGFR on Tyr845 has previously been shown to regulate the proliferation and transformation of breast cancer cells (Mueller et al, 2012;Sato et al, 2003); therefore, we assessed the localization of Src and the EGFR during invadopodia formation and examined the phosphorylation of the EGFR on Tyr845. When serum-starved cells were plated onto a gelatin matrix, Src and the EGFR were observed to colocalize at the ventral membrane of cells 20 min after plating; furthermore, Src, the EGFR and F-actin were colocalized together at immature invadopodia at 40 min after plating (Fig.…”

Section: Src Phosphorylates Egfr In a Snare-dependent Mannermentioning

confidence: 99%

SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion

Williams

Coppolino

2014

Journal of Cell Science

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Acquisition of an invasive phenotype is prerequisite for tumor metastasis. Degradation of the extracellular matrix (ECM), and subsequent invasion by tumor cells, is mediated, in part, through subcellular structures called invadopodia. Src-dependent cytoskeletal rearrangements are required to form invadopodia, and here we identify an association between Src, epidermal growth factor receptor (EGFR), and b1 integrin that facilitates invadopodia formation. The association of Src, EGFR and b1 integrin is dependent upon membrane traffic that is mediated by syntaxin13 (officially known as STX12) and SNAP23; a similar dependence on these two SNARE proteins was observed for invadopodium-based matrix degradation and cell invasion. Inhibition of SNARE function impaired the delivery of Src and EGFR to developing invadopodia, as well as the b1-integrin-dependent activation of Src and phosphorylation of EGFR on Tyr residue 845. We also identified an association between SNAP23 and b1 integrin, and inhibition of b1 integrin increased this association, whereas the interaction between syntaxin13 and SNAP23 was reduced. The results suggest that SNARE-dependent trafficking is regulated, in part, by b1 integrin and is required for the delivery of Src and EGFR to sites of invadopodia formation in order to support tumor cell invasion.

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“…Both UM-164 and dasatinib robustly reduce phosphorylation of EGFR/Tyr-845, a known site of EGFR activation by c-Src. Intriguingly, UM-164 reduced phosphorylation of EGFR/Tyr-1068, an autophosphorylation site of EGFR known to be important in TNBC oncogenesis (39). Given that neither UM-164 nor dasatinib directly inhibits EGFR, this reduction in EGFR/ Tyr-1068 phosphorylation is likely due to an indirect mechanism.…”

Section: Kinome-wide Profiling Of Um-164mentioning

confidence: 93%

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Gilani

Phadke

Bao

et al. 2016

Clinical Cancer Research

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Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.Experimental Design: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts. Results:We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC.

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EGFR Tyrosine 845 Phosphorylation-Dependent Proliferation and Transformation of Breast Cancer Cells Require Activation of p38 MAPK

Cited by 41 publications

References 27 publications

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

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