Motif mimetic of epsin perturbs tumor growth and metastasis

Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jingfang; Brophy, Megan L; Yu, Lili; Song, Kai; Silasi‐Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hyohak; Mehta-D’souza, Padmaja; Towner, Rheal A.; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, Ramesh; Chen, Hong

doi:10.1172/jci80349

Cited by 25 publications

(63 citation statements)

References 61 publications

(87 reference statements)

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“…Epsins recognize ubiquitinated VEGFR2, support its degradation and reduce VEGF signaling. As a therapeutic strategy, a synthetic peptide that blocks epsin-VEGFR2 interactions has been shown to result in dysfunctional vasculature unable to support the growing tumor [35]. The present study reports for the first time that expression of a member of the epsin family is associated with poor outcome in two common human cancers.…”

Section: Discussionmentioning

confidence: 72%

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy

et al. 2016

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BackgroundIn breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.MethodsAffymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.ResultsTen late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.ConclusionsRibosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.

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Section: Discussionmentioning

confidence: 72%

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy

et al. 2016

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“…Although receptor internalization is a recognized mechanism of signal modification, and that there have been conflicting reports that VEGFR2 internalization is necessary for signal propagation, we have demonstrated in several publications that, at least in conditions in which epsins are deficient or inhibited, VEGFR2 is capable of signaling downstream to ERK and AKT from the cell surface 9, 10, 46 . We hypothesize that interactions between different adaptor proteins may facilitate VEGFR2 internalization and incorporation into recycling signaling endosomes thereby amplifying VEGFR2 signaling cascades.…”

Section: Discussionmentioning

confidence: 82%

Selective Targeting of a Novel Epsin–VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis

Rahman

Dong

et al. 2016

Circulation Research

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Rationale We previously reported that VEGF-induced binding of VEGFR2 to epsins 1 and 2 triggers VEGFR2 degradation and attenuates VEGF signaling. The epsin ubiquitin interacting motif (UIM) was shown to be required for the interaction with VEGFR2, however the molecular determinants that govern how epsin specifically interacts with and regulates VEGFR2 were unknown. Objective The goals for the present study were (1) to identify critical molecular determinants that drive the specificity of the epsin and VEGFR2 interaction and (2) to ascertain if such determinants were critical for physiological angiogenesis in vivo. Methods and Results Structural modeling uncovered two novel binding surfaces within VEGFR2 that mediate specific interactions with epsin UIM. Three glutamic acid residues in epsin UIM were found to interact with residues in VEGFR2. Further, we found that the VEGF-induced VEGFR2-epsin interaction promoted c-Cbl-mediated ubiquitination of epsin, and uncovered a previously unappreciated ubiquitin-binding surface within VEGFR2. Mutational analysis revealed that the VEGFR2-epsin interaction is supported by VEGFR2 interacting specifically with the UIM and with ubiquitinated epsin. An epsin UIM peptide, but not a mutant UIM peptide, potentiated endothelial cell proliferation, migration and angiogenic properties in vitro, increased postnatal retinal angiogenesis, and enhanced VEGF-induced physiological angiogenesis and wound healing. Conclusions Distinct residues in the epsin UIM and VEGFR2 mediate specific interactions between epsin and VEGFR2, in addition to UIM recognition of ubiquitin moieties on VEGFR2. These novel interactions are critical for pathophysiological angiogenesis, suggesting that these sites could be selectively targeted by therapeutics to modulate angiogenesis.

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“…doxorubicin, Taxol, OKN-007). These vessels in metastasis models could be hypothesized to provide a route of tumor dissemination because of their leakiness despite the study demonstrating that the treatment impedes cancer metastasis [28]. The indicated findings provide strong in vivo evidence for endothelial epsins as druggable targets.…”

Section: Epsins As Regulators and Targets For Anti-angiogenic Cancer mentioning

confidence: 99%

“…In this capacity, loss of endothelial epsins or epsin mimetic peptide treatment leads to the accumulation of VEGFR2 cell-surface and augmentation of VEGRF2 signaling, including phosphorylation of VEGFR2, PLC-γ, Akt, and ERK—which induces nonproductive leaky angiogenesis and inhibits tumor progression (Fig. 1B-C) [24, 28]. …”

Section: Epsins As Regulators and Targets For Anti-angiogenic Cancer mentioning

confidence: 99%

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Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis

Song

Rahman

et al. 2016

Cell. Mol. Life Sci.

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VEGF-driven tumor angiogenesis has been validated as a central target in several tumor types deserving of continuous and further considerations to improve the efficacy and selectivity of current therapeutic paradigms. Epsins, a family of endocytic clathrin adaptors, have been implicated in regulating endothelial cell VEGFR2 signaling, where its inactivation leads to nonproductive leaky neo-angiogenesis and therefore impedes tumor development and progression. Targeting endothelial epsins is of special significance due to its lack of affecting other angiogenic signaling pathways or disrupting normal quiescent vessels, suggesting a selective modulation of tumor angiogenesis. This review highlights seminal findings on the critical role of endothelial epsins in tumor angiogenesis and their underlying molecular events, as well as strategies to prohibit the normal function of endogenous endothelial epsins that capitalize on these newly understood mechanisms.

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Motif mimetic of epsin perturbs tumor growth and metastasis

Cited by 25 publications

References 61 publications

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy

Selective Targeting of a Novel Epsin–VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis

Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis

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