Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation

Tanaka, Tomohiro; Zhou, Yue; Ozawa, Tatsuhiko; Okizono, Ryuya; Banba, Ayako; Yamamura, Tomohiro; Oga, Eiji; Muraguchi, Atsushi; Sakurai, Hiroaki

doi:10.1074/jbc.m117.811299

Cited by 57 publications

(78 citation statements)

References 45 publications

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“…We recently demonstrated that TNF-α-induced endocytosis occurred on inactive monomeric EGFR in a TK-independent manner using a dimer-deficient EGFR mutant (dd-EGFR) lacking extra-and intracellular dimerization sequences (9,18,23,24). We detected the cisplatin-induced phosphorylation of dd-EGFR at Ser-1015 and Ser-1047 (Fig.…”

Section: Cisplatin-induced Egfr Endocytosis Via Ser-1015 Phosphor Ylamentioning

confidence: 99%

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

et al. 2018

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Abstract. The aberrant activation of receptor tyrosine kinases (RTKs) is associated with tumor initiation in various types of human cancer, including non-small cell lung cancers (NSCLCs). Tyrosine kinase-independent non-canonical RTK regulation has also been investigated in tumor malignant alterations, including cellular stress responses. It was recently reported that the phosphorylation of epidermal growth factor receptor (EGFR) at C-terminal Ser-1015 serves a critical role in growth factor and cytokine signaling. In the present study, the role of non-canonical EGFR regulation has been investigated in NSCLC cells treated with cisplatin, a common chemotherapeutic agent. Cisplatin-induced p38 activation triggered the Ser-1015 phosphorylation of EGFR, with similar kinetics to previously reported Ser-1047 phosphorylation, in a tyrosine kinase-independent manner. In addition, phosphorylation around Ser-1015 triggered endocytosis of a dimer deficient mutant of EGFR. The non-canonical endocytosis of EGFR monomers was primarily controlled by the region around Ser-1015 only; however, Ser-1047 on internalized EGFR was equally phosphorylated. The results of the present study provide mechanistic evidence for the cisplatin-induced non-canonical regulation of EGFR.

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Section: Cisplatin-induced Egfr Endocytosis Via Ser-1015 Phosphor Ylamentioning

confidence: 99%

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

et al. 2018

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“…Evidence from our own and previous studies suggests that the ERK (partially JNK) pathway plays a pivotal role in scratch/EGFR-mediated CCL20 production. Although p38 MAPK is not directly involved in scratch-induced CCL20 production, a recent study suggests that p38 MAPK may regulate the recycling of EGFR by accelerating the latter's endocytosis [49].…”

Section: Discussionmentioning

confidence: 99%

The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients

Furue

Ito

Tanaka

et al. 2020

IJMS

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Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A–producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)–independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.

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“…However, EGFR still has serine/threonine phosphorylation sites, which also play important roles in EGFR regulation, including EGFR endocytosis. 28,29 We found that DPBA had no effect on EGFR serine/ threonine phosphorylation level, indicating that Ser/Thr phosphorylation may not be involved in DPBA-induced EGFR endocytosis ( Supplementary Fig. 2c).…”

Section: Dpba Decreases Egfr Protein Levels By Lysosomal Degradationmentioning

confidence: 90%

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

Yao

Wang

Liu

et al. 2020

Sig Transduct Target Ther

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Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

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Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation

Cited by 57 publications

References 45 publications

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

Cisplatin‑induced non‑canonical endocytosis of EGFR via p38 phosphorylation of the C‑terminal region containing Ser‑1015 in non‑small cell lung cancer cells

The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

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