Eph/ephrin molecules—a hub for signaling and endocytosis

Pitulescu, Mara E.; Adams, Ralf H.

doi:10.1101/gad.1973910

Cited by 249 publications

(217 citation statements)

References 140 publications

(184 reference statements)

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“…EphA2 also appears to be essential for Rab5 association with internalized KSHV in the early macropinosome and productive trafficking of KSHV. This observation is also supported by other studies where Eph-EphA2 complexes are implicated in different forms of endocytosis and cellular trafficking pathways (22). The factor(s) recognizing the EphA2-integrin-KSHV complex leading into macropinosome formation and sorting needs to be analyzed further.…”

Section: Discussionsupporting

confidence: 50%

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Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

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Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.virus entry | productive endocytosis | receptor tyrosine kinase

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Section: Discussionsupporting

confidence: 50%

“…Ephrins and Eph receptors modulate the endothelial cellular assembly by controlling various signaling pathways (20). Ephrin receptors have also been shown to be the center of signaling crosstalk between integrins, PI3-K, and Rho-GTPases (21,22), which are also induced during KSHV infection (3).…”

mentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

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“…The transwell studies already discussed provide direct evidence that ALDHbr cells respond to signals produced by HUVEC under hypoxia. Finally, the high expression of EphB4 suggests that ALDHbr cells may interact with endothelial cells and also regulate angiogenesis by an additional mechanism, direct cell to cell contact [51][52][53]. Interaction of ephrin receptors on one cell with cognate ephrin ligands on another can initiate angiogenic activity in both cells.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Action of Human Aldehyde Dehydrogenase Bright Cells in Therapy of Cardiovascular Diseases: Expression Analysis of Angiogenic Factors and Aldehyde Dehydrogenase Isozymes

White

Smith²,

Gentry³

et al. 2012

J Stem Cell Res Ther

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Human stem cell populations that express high aldehyde dehydrogenase activity [ALDHbr cells] have angiogenic activity in preclinical models and have been used safely to treat patients in early clinical trials. Bone marrow ALDHbr cells are being developed for therapeutic use in ischemic cardiovascular diseases. The mechanisms by which ALDHbr cells repair ischemic tissue are unknown, but available data suggest that angiogenic factors released by ALDHbr cells are involved. Gene expression studies were performed, and bone marrow ALDHbr cells were found to express 69 of 84 angiogenic factors tested. The 25 most highly expressed genes included soluble cytokines and growth factors, cytokine receptors, extracellular matrix proteins, and cell-cell signaling receptors. ALDHdim bone marrow cells that do not express high levels of ALDH and that have no angiogenic activity in preclinical models expressed a different group of genes. CD105 and Ephrin B4 transcripts were expressed about 65-fold more highly in ALDHbr than ALDHdim cells, and expression of these proteins was demonstrated in ALDHbr cells by flow cytometry. Expression analysis probing all 19 ALDH isozymes and immunofluorescence both demonstrated that ALDH1A1, an enzyme that can generate retinoic acids from retinaldehyde, was the ALDH isozyme most highly over

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“…Rather than being an activating step, ADAM cleavage is required to switch off signaling. Regulation of axonal guidance requires cell-cell repulsion, driven by the interaction between Eph receptors on one cell and membrane-tethered ephrin ligand on an adjacent cell (Pitulescu and Adams 2010). As the Eph:ephrin interaction is multivalent and high affinity, receptor: ligand complexes favor cell -cell adhesion.…”

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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Eph/ephrin molecules—a hub for signaling and endocytosis

Cited by 249 publications

References 140 publications

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Mechanisms of Action of Human Aldehyde Dehydrogenase Bright Cells in Therapy of Cardiovascular Diseases: Expression Analysis of Angiogenic Factors and Aldehyde Dehydrogenase Isozymes

Regulation of Receptor Tyrosine Kinase Ligand Processing

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