EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans
Ephrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in viv...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/165 |
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| author | Di Chen Martijn A. Van der Ent Nathaniel L. Lartey Philip D. King |
| author_facet | Di Chen Martijn A. Van der Ent Nathaniel L. Lartey Philip D. King |
| author_sort | Di Chen |
| collection | DOAJ |
| description | Ephrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in vivo have pointed to a critical role for Ephrin receptor B4 (EPHB4) as a regulator of blood and lymphatic vascular development and function. However, in this role, EPHB4 appears to act not as a classical growth factor receptor but instead functions to dampen the activation of the Ras-mitogen activated protein signaling (MAPK) pathway induced by other growth factor receptors in endothelial cells (EC). To inhibit the Ras-MAPK pathway, EPHB4 interacts functionally with Ras p21 protein activator 1 (RASA1) also known as p120 Ras GTPase-activating protein. Here, we review the evidence for an inhibitory role for an EPHB4–RASA1 interface in EC. We further discuss the mechanisms by which loss of EPHB4–RASA1 signaling in EC leads to blood and lymphatic vascular abnormalities in mice and the implications of these findings for an understanding of the pathogenesis of vascular anomalies in humans caused by mutations in <i>EPHB4</i> and <i>RASA1</i> genes. Last, we provide insights into possible means of drug therapy for EPHB4- and RASA1-related vascular anomalies. |
| first_indexed | 2024-03-11T08:17:44Z |
| format | Article |
| id | doaj.art-3dbfde3b3fd443bfbb2003f52ec33eb5 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:17:44Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-3dbfde3b3fd443bfbb2003f52ec33eb52023-11-16T22:35:55ZengMDPI AGPharmaceuticals1424-82472023-01-0116216510.3390/ph16020165EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in HumansDi Chen0Martijn A. Van der Ent1Nathaniel L. Lartey2Philip D. King3Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USAEphrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in vivo have pointed to a critical role for Ephrin receptor B4 (EPHB4) as a regulator of blood and lymphatic vascular development and function. However, in this role, EPHB4 appears to act not as a classical growth factor receptor but instead functions to dampen the activation of the Ras-mitogen activated protein signaling (MAPK) pathway induced by other growth factor receptors in endothelial cells (EC). To inhibit the Ras-MAPK pathway, EPHB4 interacts functionally with Ras p21 protein activator 1 (RASA1) also known as p120 Ras GTPase-activating protein. Here, we review the evidence for an inhibitory role for an EPHB4–RASA1 interface in EC. We further discuss the mechanisms by which loss of EPHB4–RASA1 signaling in EC leads to blood and lymphatic vascular abnormalities in mice and the implications of these findings for an understanding of the pathogenesis of vascular anomalies in humans caused by mutations in <i>EPHB4</i> and <i>RASA1</i> genes. Last, we provide insights into possible means of drug therapy for EPHB4- and RASA1-related vascular anomalies.https://www.mdpi.com/1424-8247/16/2/165Ephrin receptor B4RASA1Ras-MAPK pathwaycapillary malformation arteriovenous malformationlymphatic malformationangiogenesis |
| spellingShingle | Di Chen Martijn A. Van der Ent Nathaniel L. Lartey Philip D. King EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans Pharmaceuticals Ephrin receptor B4 RASA1 Ras-MAPK pathway capillary malformation arteriovenous malformation lymphatic malformation angiogenesis |
| title | EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans |
| title_full | EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans |
| title_fullStr | EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans |
| title_full_unstemmed | EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans |
| title_short | EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans |
| title_sort | ephb4 rasa1 mediated negative regulation of ras mapk signaling in the vasculature implications for the treatment of ephb4 and rasa1 related vascular anomalies in humans |
| topic | Ephrin receptor B4 RASA1 Ras-MAPK pathway capillary malformation arteriovenous malformation lymphatic malformation angiogenesis |
| url | https://www.mdpi.com/1424-8247/16/2/165 |
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