β2‐Chimaerin binds to EphA receptors and regulates cell migration

Takeuchi, Shinichi; Yamaki, Nao; Iwasato, Takuji; Negishi, Manabu; Katoh, Hironori

doi:10.1016/j.febslet.2009.03.032

Cited by 21 publications

(18 citation statements)

References 19 publications

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“…The chimaerin Rac-GAPs represent a family of DAG/phorbol ester receptors that have recently gained significant attention due to their implications in development, neuritogenesis, and cancer progression (6-11). Similar to PKCs, chimaerins can redistribute to membranes in cellular models in response to phorbol ester stimulation, an effect mediated by direct ligand binding to the C1 domain (4, 12, 15).…”

Section: Discussionmentioning

confidence: 99%

Biochemical Characterization of Hyperactive β2-Chimaerin Mutants Revealed an Enhanced Exposure of C1 and Rac-GAP Domains

et al. 2009

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Recent studies established that the Rac-GAP β2-chimaerin plays important roles in development, neuritogenesis, and cancer progression. A unique feature of β2-chimaerin is that it can be activated by phorbol esters and the lipid second messenger diacylglycerol (DAG), which bind with high affinity to its C1 domain and promote β2-chimaerin translocation to membranes, leading to the inactivation of the small G-protein Rac. Crystallographic evidence and cellular studies suggest that β2-chimaerin remains in an inactive conformation in the cytosol with the C1 domain inaccessible to ligands. We developed a series of β2-chimaerin point mutants in which intramolecular contacts that occlude the C1 domain have been disrupted. These mutants showed enhanced translocation in response to phorbol 12-myristate 13-acetate (PMA) in cells. Binding assays using [ 3 H]phorbol 12, 13-dibutyrate ([ 3 H] PDBu) revealed that internal contact mutants have a reduced acidic phospholipid requirement for phorbol ester binding. Moreover, disruption of intramolecular contacts enhances binding of β2-chimaerin to acidic phospholipid vesicles and confers enhanced Rac-GAP activity in vitro. These studies suggest that β2-chimaerin must undergo a conformational rearrangement in order to expose its lipid binding sites and become activated. Keywordsβ2-chimaerin; C1 domain; phorbol esters; Rac Rac, a small GTPase that belongs to the Rho family, mediates signals by tyrosine-kinase and G-protein-coupled receptors and is known to play key roles in the regulation of actin dynamics, cell cycle progression, adhesion, and migration. This small G-protein cycles between active (GTP-bound) and inactive (GDP-bound) conformations. Upon receptor stimulation, Rac Guanine-nucleotide Exchange Factors (Rac-GEFs) promote GTP loading onto Rac, which adopts a conformation capable of activating downstream effectors such as Pak kinases. Rac inactivation is mediated through GTPase Activating Proteins (GAPs) that promote the hydrolysis of GTP from activated Rac (1,2). One of the Rac-GAP families that received significant attention in the last years is the chimaerin family, a group of four related GAPs

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Section: Discussionmentioning

confidence: 99%

Biochemical Characterization of Hyperactive β2-Chimaerin Mutants Revealed an Enhanced Exposure of C1 and Rac-GAP Domains

et al. 2009

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“…Recruitment of the lipid phosphatase SHIP2 by EPHA2 inhibits RAC1 and EPHA2 internalization182. EPHA4 inhibits RAC1 through Chimaerins1,183. EPHA2-mediated inhibition of ADP-ribosylation factor 6 (ARF6) in epithelial cells inhibits epithelial-to-mesenchymal transition (EMT)170.…”

Section: Figures and Tablesmentioning

confidence: 99%

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

2010

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The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumor blood vessels, which suggest important roles for their bidirectional signals in multiple aspects of cancer development and progression. Eph gene mutations likely also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth and migration/invasion of cancer cells in culture as well as tumor growth, invasiveness, angiogenesis, and metastasis in vivo. However, Eph signaling activities in cancer appear to be complex, and are characterized by puzzling dichotomies. The Eph receptors nevertheless represent promising new therapeutic targets in cancer.Eph receptors and their ephrin ligands together form an important cell communication system with widespread roles in normal physiology and disease pathogenesis 1 . Links between Eph receptors and cancer date back to the first identified Eph family member 2 . EphA1 was cloned from a carcinoma cell line in a screen for novel oncogenic tyrosine kinases. The novel receptor was found to be upregulated in tumor versus normal tissues and its overexpression caused the oncogenic transformation of NIH3T3 fibroblasts 2,3 . The first Eph receptor-interacting (ephrin) ligand, EPHRIN-A1, was also identified from cancer cells a few years later 4 . The evidence implicating Eph receptors and ephrins in cancer is now extensive, and continues to grow.The activities of the Eph system in cancer are complex, and intriguing in their paradoxical effects. For example, multiple Eph receptors and/or ephrins are present in essentially all types of cancer cells. However, not only increased but also decreased Eph expression has been linked to cancer progression. Consistent with this dichotomy, there is good evidence that Eph receptors and ephrins can both promote and inhibit tumorigenicity. The factors responsible for these divergent activities are only beginning to be uncovered.Following a brief overview of the Eph and ephrin families and their bidirectional signaling mechanisms, the factors that regulate their expression and the remarkable multiplicity of their roles in cancer will be discussed, and the strategies under evaluation to target the Eph system for cancer therapy outlined. Other reviews provide more in depth information on Eph signaling mechanisms in development and adult physiology 1,[5][6][7][8] . Eph and ephrin familiesIn the human genome there are 9 EphA receptors, which promiscuously bind 5 glycosylphosphatidylinositol (GPI)-linked ephrin-A ligands, and 5 EphB receptors, which NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2010 September 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript promiscuously bind 3 transmembrane ephrin-B ligands 5 . Exceptions are the EPHA4 and EPHB2 receptors, which can also bind ephrin-Bs and EPHRIN-A5, respectively, and EPHB4, which preferentially binds only EPHRIN-B2. Eph receptors typically interact with the cell surface...

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“…However, a-chimerin does not seem to impact on EphA4-mediated axon guidance within the anterior commissure [296]. b2-Chimerin also binds to the kinase domains of EphA2 and EphA4, and has been proposed to act in a similar way as a2-chimerin [297]. In addition, LMW-PTPmediated dephosphorylation of p190RhoGAP leads to RhoA activation, important in destabilisation of adherens junctions [298].…”

Section: Gefs and Gaps Of Rho Family Gtpases Involved In Eph Signallingmentioning

confidence: 99%

Eph-dependent cell-cell adhesion and segregation in development and cancer

Nievergall

Lackmann

Janes

2011

Cell. Mol. Life Sci.

107

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Numerous studies attest to essential roles for Eph receptors and their ephrin ligands in controlling cell positioning and tissue patterning during normal and oncogenic development. These studies suggest multiple, sometimes contradictory, functions of Eph-ephrin signalling, which under different conditions can promote either spreading and cell-cell adhesion or cytoskeletal collapse, cell rounding, de-adhesion and cell-cell segregation. A principle determinant of the balance between these two opposing responses is the degree of receptor/ligand clustering and activation. This equilibrium is likely altered in cancers and modulated by somatic mutations of key Eph family members that have emerged as candidate cancer markers in recent profiling studies. In addition, cross-talk amongst Ephs and with other signalling pathways significantly modulates cell-cell adhesion, both between and within Eph- and ephrin-expressing cell populations. This review summarises our current understanding of how Eph receptors control cell adhesion and morphology, and presents examples demonstrating the importance of these events in normal development and cancer.

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β2‐Chimaerin binds to EphA receptors and regulates cell migration

Cited by 21 publications

References 19 publications

Biochemical Characterization of Hyperactive β2-Chimaerin Mutants Revealed an Enhanced Exposure of C1 and Rac-GAP Domains

Biochemical Characterization of Hyperactive β2-Chimaerin Mutants Revealed an Enhanced Exposure of C1 and Rac-GAP Domains

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Eph-dependent cell-cell adhesion and segregation in development and cancer

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