Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Georgakopoulos, Anastasios; Litterst, Claudia; Ghersi, Enrico; Baki, Lia; Xu, Chi-jie; Serban, George; Robakis, Nikolaos K.

doi:10.1038/sj.emboj.7601031

Cited by 145 publications

(185 citation statements)

References 57 publications

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“…[3][4][5][6][7] In general, the EPH kinases interact with their EFN ligands on neighboring cells, because EPHs and EFNs are all cell surface molecules. 2 These molecules could be cleaved from the cell surface by enzymes such as ADAM10, 8,9 an unspecified matrix metalloproteinase, 10 or γ-secretase; 11 therefore, it is possible that the shed soluble fragments of EPH and EFN might be able to influence cells and tissues at a distance by blocking the interaction of EPHs and EFNs there.…”

Section: Introductionmentioning

confidence: 99%

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

et al. 2016

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Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3′ region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans. European Journal of Human Genetics (2016) 24, 1817-1825; doi:10.1038/ejhg.2016.105; published online 17 August 2016 INTRODUCTION Erythropoietin-producing hepatocellular kinases (EPH) are the largest family of receptor tyrosine kinases. In the basis of sequence homology, they are divided into A and B subfamilies. 1 Their ligands, called ephrins (EFNs), are also cell surface molecules. 2 EFNs are also divided into A and B subfamilies, based on the way they anchor on the cell surface: the A subfamily anchors on the cell surface through glycophosphatidylinositol, and the B subfamily, through a transmembrane domain. 2 The interactions between EPH kinases and EFNs are promiscuous, but EPHA kinases preferably interact with EFNA ligands, and EPHB kinases with EFNB ligands, which have three members, EFNB1, EFNB2 and EFNB3. 2 Although EPH members and EFN members share homology with their respective members, each member has its distinct function in different cellular processes. [3][4][5][6][7] In general, the EPH kinases interact with their EFN ligands on neighboring cells, because EPHs and EFNs are all cell surface molecules. 2 These molecules could be cleaved from the cell surface by enzymes such as ADAM10, 8,9 an unspecified matrix metalloproteinase, 10 or γ-secretase; 11 therefore, it is possible that the shed soluble fragments of EPH and EFN might be able to influence cells and tissues at a distance by blocking the interaction of EPHs and EFNs there.

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Section: Introductionmentioning

confidence: 99%

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

et al. 2016

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“…As well as triggering RTK activity in the receptor-bearing cells, a signal is triggered in the ligand-expressing cell (Georgakopoulos et al 2006). This is important for the role of ephrinB2 in cardiac valve maturation and axon path finding (Cowan et al 2004).…”

Section: Cleavage Of Ephrinsmentioning

confidence: 99%

Regulation of Receptor Tyrosine Kinase Ligand Processing

Adrain

Freeman

2014

Cold Spring Harbor Perspectives in Biology

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A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.C ells must talk to one another. This principle applies throughout the tree of life: from unicellular bacteria, to the trillions of cells that coordinate to make a mammal. Communication between cells requires dedicated machinery, capable of relaying information across membranes. Transmembrane proteins are therefore essential for signaling. Understanding how this is regulated is paramount. In mammals, receptor tyrosine kinases (RTKs) and their ligands are important examples of such machinery (Schlessinger 2000), controlling many biological processes including development, immunity, tissue repair, and metabolic homeostasis (Ullrich and Schlessinger 1990). They are transmembrane proteins with an extracellular ligand-binding motif and an intracellular kinase domain. As discussed in other chapters, a common mode of RTK activation involves receptor dimerization induced by ligand binding (Lemmon and Schlessinger 2010).Regulated access of ligand to receptor, over distance and time, is key to controlling signaling. Ligands are frequently synthesized as transmembrane forms; when they remain membrane-tethered and cannot diffuse, the range over which they can operate is limited to adjacent cells (Massague and Pandiella 1993; Singh and 1 Present address: Instituto

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“…Several mechanisms are known to regulate the tyrosine phosphorylation of ephrinBs. First, EphB receptor stimulates a metalloproteinase cleavage of ephrinB ligands, producing a C-terminal fragment that is further processed by presenilin 1/γ-secretase [28,80]. The final peptide product binds Src and inhibits its association with a negative Src regulator termed cterminal Src kinase (Csk), allowing further activation of Src [28].…”

Section: The Forward and Reverse Signalingmentioning

confidence: 99%

“…First, EphB receptor stimulates a metalloproteinase cleavage of ephrinB ligands, producing a C-terminal fragment that is further processed by presenilin 1/γ-secretase [28,80]. The final peptide product binds Src and inhibits its association with a negative Src regulator termed cterminal Src kinase (Csk), allowing further activation of Src [28]. Second, after tyrosine phosphorylation, ephrinB ligands recruit a phosphotyrosine phosphotase PTP-BL through their PDZ-binding domain and are subsequently dephosphorylated [65].…”

Section: The Forward and Reverse Signalingmentioning

confidence: 99%

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Bidirectional ephrin/Eph signaling in synaptic functions

Aoto¹,

Chen²

2007

Brain Research

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Eph receptors, the largest family of receptor tyrosine kinases, and their membrane bound ligands, the ephrins, are involved in multiple developmental and adult processes within and outside of the nervous system. Bi-directional signaling from both the receptor and the ligand is initiated by ephrinEph binding upon cell-cell contact, and involves interactions with distinct subsets of downstream signaling molecules related to specific functions. In the CNS, Ephs and ephrins act as attractive/ repulsive, migratory, and cell adhesive cues during development and participate in synaptic functions in adult animals. In this review, we will focus on recent findings highlighting the functions of ephrin/ Eph signaling in dendritic spine morphogenesis, synapse formation, and synaptic plasticity.

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Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Cited by 145 publications

References 57 publications

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

Regulation of Receptor Tyrosine Kinase Ligand Processing

Bidirectional ephrin/Eph signaling in synaptic functions

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