SHP2 protects endothelial cell barrier through suppressing VE‐cadherin internalization regulated by MET‐ARF1

Zhang, Jie; Huang, Jiaqi; Qi, Tongyun; Huang, Yizhou; Lu, Yuting; Zhan, Tianwei; Gong, Hui; Zhu, Zhengyi; Shi, Yueli; Yu, Luyang; Zhang, Xue; Cheng, Hongqiang; Ke, Yuehai

doi:10.1096/fj.201800284r

Cited by 20 publications

(18 citation statements)

References 51 publications

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“…We found that SHP2 silencing effectively inhibited endothelial cell (BMEC) proliferation (Fig 2G). This effect is consistent with previous observation showing that SHP2 depletion from primary endothelial cells reduces cell proliferation, induce cell death (Mannell et al, 2008), and destabilize endothelial cell junctions reducing endothelial cell barrier functions (Zhang et al, 2019). However, SHP2 depletion from B16F10 cells did not reduce B16F10 cell proliferation (Fig 2G).…”

Section: Inhibition Of Shp2 Tyrosine Phosphatase Compromises Endothelial Cell Viabilitysupporting

confidence: 93%

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

et al. 2021

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The tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits proapoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumor types selected for SHP2-independent tumor cell growth promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints, or recruiting macrophages. We also show that inhibiting the Angiopoietin/TIE2/ AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/TIE2 inhibitors hold promise to effectively target the tumor endothelium.

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Section: Inhibition Of Shp2 Tyrosine Phosphatase Compromises Endothelial Cell Viabilitysupporting

confidence: 93%

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

et al. 2021

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“…These results show that SHP099 reduces endothelial cell proliferation and induces cell death in endothelial cells. Consistent with these results, depletion of SHP2 from primary endothelial cells was reported to reduce cell proliferation, induce cell death (22), and destabilize endothelial cell junctions reducing endothelial cell barrier functions (21).…”

Section: Ephrinb2/shp2 and Ang2/tie2 Activity In Vascular Endothelialsupporting

confidence: 65%

“…Genetic experiments in mice showed that SHP2 is required for the formation of a hierarchically organized vessel network in the mouse yolk sac, linking SHP2 to regulation of post-angiogenic/vasculogenic remodeling events (46). Similarly, the knockout of SHP2 in endothelial cells caused embryonic hemorrhage and death attributed to disruption of endothelial cell junctions (21). Experiments in vitro suggested that SHP2 regulates endothelial adhesive functions and migration stemming from SHP2 binding to the intracellular domain of endothelial platelet-derived growth factor receptor-b (PDGFR-b), VE-cadherin and PECAM-1 (47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Experiments in vitro suggested that SHP2 regulates endothelial adhesive functions and migration stemming from SHP2 binding to the intracellular domain of endothelial platelet-derived growth factor receptor-b (PDGFR-b), VE-cadherin and PECAM-1 (47,48). The knockdown of SHP2 transiently reduced FGF2+VEGF-dependent endothelial cell viability in vitro and ex vivo (22), delayed vessel regeneration in a mouse skin wounding model (49) and increased endothelial monolayer permeability (21). Also, SHP2 promoted VEGF-dependent ERK1/2 signaling (50), consistent with the role of EphrinB2-SHP2 signaling as a key regulator of VEGFR2 internalization and ERK signaling (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…Also, SHP099 reduced endothelial cell content of vascular endothelial (VE)-cadherin ( Supplementary Fig. 3D), an endothelial pro-survival protein (20) identified as a mediator of SHP2 protective function in endothelial cells (21). Furthermore, SHP2 increased the levels of the pro-apoptotic JNK3 in BMEC and HUVEC ( Supplementary Fig.…”

Section: Ephrinb2/shp2 and Ang2/tie2 Activity In Vascular Endothelialmentioning

confidence: 92%

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Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

Wang

Salvucci

Ohnuki

et al. 2020

Preprint

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The tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumors selected for SHP2-independent tumor-cell growth, promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor hypoxia and necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints or recruiting anti-tumor macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/Tie2 inhibitors hold promise to effectively target the tumor endothelium.

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SHP2‐Triggered Endothelial Cell Activation Fuels Estradiol‐Independent Endometrial Sterile Inflammation

Pan,

Qu,

Fang

et al. 2024

Advanced Science

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Sterile inflammation occurs in various chronic diseases due to many nonmicrobe factors. Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen‐induced sterile inflammation regulates EH remains unclear. Here, a single‐cell RNA‐Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1β and TNFα from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell–macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA‐Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1Tyr380. This event activates downstream activator protein 1 (AP‐1) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial‐specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol‐driven acute inflammation to macrophage‐amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen‐related diseases.

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SHP2 protects endothelial cell barrier through suppressing VE‐cadherin internalization regulated by MET‐ARF1

Cited by 20 publications

References 51 publications

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

SHP2‐Triggered Endothelial Cell Activation Fuels Estradiol‐Independent Endometrial Sterile Inflammation

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