p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047

Adachi, Seiji; Natsume, Hideo; Yamauchi, Junko; Matsushima‐Nishiwaki, Rie; Joe, Andrew K.; Moriwaki, Hisataka; Kozawa, Osamu

doi:10.1016/j.canlet.2008.11.034

Cited by 35 publications

(34 citation statements)

References 24 publications

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“…Our findings show in pancreatic cancer cells that: i) EGFR is targeted by HSP90 inhibitors; ii) HSP90 inhibitors induce activation of p38 MAPK; iii) the inhibition of HSP90 induces the EGFR phosphorylation at Ser1046/7, a site which is reported to play an important role in its desensitization; and iv) p38 MAPK regulates desensitization of EGFR via its phosphorylation at Ser1046/7. Our present study in pancreatic cancer cells is consistent with our previous report showing that p38 MAPK directs EGFR toward desensitization via its phosphorylation at Ser1046/7 (22), because in the present study we found that HSP90 inhibitors induced p38 MAPK, leading to EGFR phosphorylation at Ser1046/7.…”

Section: Discussionsupporting

confidence: 82%

“…Moreover, mutations of Ser1046/7 are reported to cause a marked inhibition of the EGFstimulated endocytosis and desensitization of cell surface receptors (20). In addition, we have recently reported that p38 mitogen-activated protein kinase (MAPK) controls EGFR desensitization via phosphorylation at Ser1046/7 (22), suggesting that serine phosphorylation of EGFR or p38 MAPK activation might be considered a new therapeutic target especially to counter cancer cells of the colon, lung, pancreas and breast that highly express EGFR.…”

Section: Introductionmentioning

confidence: 99%

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HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

Adachi

Yasuda²,

Nakashima³

et al. 2010

Oncol Rep

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Abstract. Heat shock protein (HSP) 90 is known to be a molecular chaperone whose association is required for the stability and function of oncogenic protein including epidermal growth factor receptor (EGFR) that promotes cancer cell growth. Therefore, HSP90 is a promising target for therapy against cancer including in the pancreas, some of which are highly dependent on EGFR. We investigated the effects of HSP90 inhibitors on cytotoxicity and desensitization of EGFR in human pancreatic cancer cells (KP3, BxPc3 and AsPc1). 17-allylamino-17-demethoxy-geldanamycin (17-AAG), an inhibitor of HSP90, caused desensitization of EGFR in a time-dependent manner, concurrently inducing phosphorylation of EGFR at Ser1046/ 1047 (Ser1046/7), a site which plays an important role in EGFR desensitization in these pancreatic cancer cells. We also found similar effects in KP3 cells treated with other HSP90 inhibitors, geldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG). In KP3 cells, 17-AAG induced activation of either p44/p42 mitogenactivated protein kinase (MAPK) or p38 MAPK. Interestingly, whereas the inhibition of p44/p42 MAPK attenuated neither phosphorylation of EGFR at Ser1046/7 nor desensitization of EGFR, the phosphorylation at Ser1046/7 induced by 17-AAG was markedly attenuated by the inhibition of p38 MAPK, indicating that p38 MAPK induced this phosphorylation. Moreover, the inhibition of p38 MAPK significantly attenuated 17-AAG-induced EGFR desensitization. These results strongly suggest that EGFR phosphorylation at Ser1046/7 via activation of p38 MAPK induced by HSP90 inhibitors plays a pivotal role in EGFR desensitization in human pancreatic cancer cells.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

Adachi

Yasuda²,

Nakashima³

et al. 2010

Oncol Rep

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“…3 that UV-C caused a marked phosphorylation of EGFR at Ser-1046/7; however, UV-C failed to induce phosphorylation at Tyr-1045, the major c-Cbl binding site, as well as Tyr-1068, the Grb2 adaptor protein-binding site (8), in contrast to the prominent phosphorylation induced by EGF as we have previously shown (25). Moreover, although UV-C caused activation of p44/p42 MAPK, p38 MAPK, or SAPK/JNK (Fig.…”

Section: Discussionmentioning

confidence: 39%

“…We have recently reported that phosphorylation of EGFR at serine 1046/7 via activation of p38 MAPK plays a pivotal role in down-regulation of EGFR induced by (Ϫ)-epigallocatechin gallate (24), anisomycin (25), and HSP90 inhibitor (26). Moreover, there is an evidence that cisplatin also induces EGFR internalization, which is mediated by p38 MAPK-dependent phosphorylation of the receptor at threonine 669 (20).…”

Section: Members Of the Egf Receptor (Egfr)mentioning

confidence: 99%

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Ultraviolet Irradiation Can Induce Evasion of Colon Cancer Cells from Stimulation of Epidermal Growth Factor

Adachi

Yasuda

Nakashima

et al. 2011

Journal of Biological Chemistry

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Receptor down-regulation is the most prominent regulatory system of EGF receptor (EGFR) signal attenuation and a critical target for therapy against colon cancer, which is highly dependent on the function of the EGFR. In this study, we investigated the effect of ultraviolet-C (UV-C) on down-regulation of EGFR in human colon cancer cells (SW480, HT29, and DLD-1). UV-C caused inhibition of cell survival and proliferation, concurrently inducing the decrease in cell surface EGFR and subsequently its degradation. UV-C, as well as EGFR kinase inhibitors, decreased the expression level of cyclin D1 and the phosphorylated level of retinoblastoma, indicating that EGFR down-regulation is correlated to cell cycle arrest. Although UV-C caused a marked phosphorylation of EGFR at Ser-1046/1047, UV-C also induced activation of p38 MAPK, a stress-inducible kinase believed to negatively regulate tumorigenesis, and the inhibition of p38 MAPK canceled EGFR phosphorylation at Ser-1046/1047, as well as subsequent internalization and degradation, suggesting that p38 MAPK mediates EGFR down-regulation by UV-C. In addition, phosphorylation of p38 MAPK induced by UV-C was mediated through transforming growth factor-␤-activated kinase-1. Moreover, pretreatment of the cells with UV-C suppressed EGF-induced phosphorylation of EGFR at tyrosine residues in addition to cell survival signal, Akt. Together, these results suggest that UV-C irradiation induces the removal of EGFRs from the cell surface that can protect colon cancer cells from oncogenic stimulation of EGF, resulting in cell cycle arrest. Hence, UV-C might be applied for clinical strategy against human colon cancers. Members of the EGF receptor (EGFR)2 family, which are frequently overexpressed in several types of human cancers, including cancers of the lung (1), head and neck (2), prostate (3), breast (4), pancreas (5), and colon (6), have been associated with abnormal growth of these tumors. It is well known that exposure of cells to EGF results in rapid autophosphorylation of EGFR molecules at the cell surface (7-10), which upon activation lead to cell proliferation, motility, and enhanced survival (11). There are several mechanisms by which EGFR becomes oncogenic including: 1) increased EGFR expression levels, 2) autocrine and/or paracrine growth factor loops, 3) heterodimerization with other EGFR family members and crosstalk with heterologous receptor systems, 4) defective receptor down-regulation, and 5) activating mutations (12). In clinical trials, increasing evidence shows the efficacy of EGFR-targeted agents, including monoclonal antibodies on the one hand and tyrosine kinase inhibitors on the other (13).Following activation, the ligand-receptor complexes are internalized and then enter endosomes, where the receptors and their ligands are sorted to various intracellular destinations (14). Thus, some receptors can be recycled back to the cell surface via early endosomes, and others are targeted to late endosomes and lysosomes for proteolytic degradation. There is increasin...

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Glabridin inhibits osteosarcoma migration and invasion via blocking the p38‐ and JNK‐mediated CREB–AP1 complexes formation

Jie

Xie

Zhao

et al. 2018

Journal Cellular Physiology

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Osteosarcoma is the most common bone malignancy, and it seriously affects the quality of life of affected children and adolescents. Glabridin (GLA), a major component of licorice root extract, has been reported to exert antitumor effects against a variety of tumor types; however, its effects on osteosarcoma have not been elucidated. In the current study, we investigate the effects and potential antimetastatic mechanisms of GLA on osteosarcoma in vitro and in vivo. Flow cytometry showed that GLA induced G2/M cell cycle phase arrest and promoted cell apoptosis. Transwell and wound-healing assays showed that GLA significantly decreased the migration and invasion of osteosarcoma cells. Further western blotting and quantitative real-time polymerase chain reaction showed that the expression of matrix metalloproteinase (MMP)-2 and MMP-9 in MG63 and HOS cells were reduced after GLA treatment. Moreover, western blotting demonstrated that GLA downregulated the phosphorylation of p38 mitogen-activated protein kinases and c-Jun N-terminal kinase. A coimmunoprecipitation assay illustrated that formation of cAMP response element-binding protein (CREB)-activating protein 1 (AP1) complexes and the DNA binding activities of CREB and AP1 in MG63 and HOS cells were impaired following treatment with GLA. Finally, GLA inhibited tumor growth and suppressed osteosarcoma cell metastasis in vivo. Overall, our findings highlight the potential of GLA as a therapeutic agent for the prevention and treatment of tumor metastasis.

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p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047

Cited by 35 publications

References 24 publications

HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

Ultraviolet Irradiation Can Induce Evasion of Colon Cancer Cells from Stimulation of Epidermal Growth Factor

Glabridin inhibits osteosarcoma migration and invasion via blocking the p38‐ and JNK‐mediated CREB–AP1 complexes formation

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