A role of the SAM domain in EphA2 receptor activation

Shi, Xiaojun; Hapiak, Vera; Zheng, Junchao; Muller‐Greven, Jeannine; Bowman, Deanna; Lingerak, Ryan; Buck, Matthias; Wang, Bing Cheng; Smith, Adam W.

doi:10.1038/srep45084

Cited by 42 publications

(51 citation statements)

References 47 publications

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“…Relevant to this, the truncation of the SAM domain induced autophosphorylation in the activation loop of EphA2 in cells [29,32], whereas the truncation of the SAM domain in EphA3 exhibited decreased activation loop autophosphorylation [31], suggesting an intramolecular regulatory role of the Eph SAM domain. The increased receptor clustering and phosphorylation observed upon deletion of the SAM domain on EphA2 and EphB2 dimerisation [28][29][30] seems to be counter-intuitive as the SAM domain is a known dimerisation domain predicted to favour Eph receptor dimerisation/oligomerisation. One possibility to reconcile this discrepancy is that the SAM domain may impose steric hindrance on the kinase domain and the kinase domain could also be a major intracellular dimerisation determinant.…”

Section: Pbm Intracellularlymentioning

confidence: 74%

“…Truncation of the SAM domain was shown to promote EphA2 and EphB2 homo-dimerisation and clustering at the plasma membrane, respectively [28][29][30], although opposing findings suggested that the presence of the SAM domain enhanced EphA3 dimerisation in cells [31]. Relevant to this, the truncation of the SAM domain induced autophosphorylation in the activation loop of EphA2 in cells [29,32], whereas the truncation of the SAM domain in EphA3 exhibited decreased activation loop autophosphorylation [31], suggesting an intramolecular regulatory role of the Eph SAM domain. The increased receptor clustering and phosphorylation observed upon deletion of the SAM domain on EphA2 and EphB2 dimerisation [28][29][30] seems to be counter-intuitive as the SAM domain is a known dimerisation domain predicted to favour Eph receptor dimerisation/oligomerisation.…”

Section: Pbm Intracellularlymentioning

confidence: 99%

“…4a) of the SAM domain is able to recruit SH2 domain-containing proteins, such as the adapter proteins Grb7, Grb10 and lowmolecular-weight protein tyrosine phosphatase [24][25][26][27]. Truncation of the SAM domain was shown to promote EphA2 and EphB2 homo-dimerisation and clustering at the plasma membrane, respectively [28][29][30], although opposing findings suggested that the presence of the SAM domain enhanced EphA3 dimerisation in cells [31]. Relevant to this, the truncation of the SAM domain induced autophosphorylation in the activation loop of EphA2 in cells [29,32], whereas the truncation of the SAM domain in EphA3 exhibited decreased activation loop autophosphorylation [31], suggesting an intramolecular regulatory role of the Eph SAM domain.…”

Section: Pbm Intracellularlymentioning

confidence: 99%

“…The JM region and the SAM domain linker therefore seem to be critical allosteric regulatory elements, with their spatial organisation dictating Eph receptor tyrosine kinase activation. In addition to the regulatory role of the SAM domain linker, it is very likely that the SAM domain itself directly impacts on the conformation of the kinase domain and hence regulates its kinase activity [28].…”

Section: Pbm Intracellularlymentioning

confidence: 99%

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Eph receptor signalling: from catalytic to non-catalytic functions

et al. 2019

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Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that drive Eph receptor signalling, and investigates the contribution of intra-and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. Throughout this review, we carefully analyse and reconcile the existing/conflicting data in the field, to allow researchers to further the current understanding of Eph receptor signalling. Eph receptors and ephrin ligands: an overview Receptor tyrosine kinases (RTKs) are a major type of membrane receptors, which govern cell proliferation, differentiation and mobility [1]. Deregulation of RTK signalling pathways leads to many diseases, such as cancers and developmental disorders [2]. The erythropoietin-producing hepatoma (Eph) receptor subfamily is the largest amongst the RTKs with 14 members classified into type A and type B. Compared with other RTKs, Eph receptors share

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Section: Pbm Intracellularlymentioning

confidence: 74%

Section: Pbm Intracellularlymentioning

confidence: 99%

Section: Pbm Intracellularlymentioning

confidence: 99%

Section: Pbm Intracellularlymentioning

confidence: 99%

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Eph receptor signalling: from catalytic to non-catalytic functions

et al. 2019

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“…Ligand binding causes a clustering of the Eph receptors, leading to the opening of an activation loop, and a subsequent tyrosine phosphorylation (shown in green) of the kinase domain. SAM domain offers a docking surface for downstream signaling and is reported to be involved in receptor oligomerization (Shi et al, 2017). RBD, Receptor-Binding Domain; LBD, Ligand-Binding Domain; CRD, Cysteine-Rich Domain; FN, Fibronectin III domain; Y-P, Phospho-Tyrosine; SAM, Sterile Alpha Motif.…”

Section: Figurementioning

confidence: 99%

Therapeutic potential of targeting the Eph/ephrin signaling complex

Saha

Robev

Mason

et al. 2018

The International Journal of Biochemistry & Cell Biology

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The Eph-ephrin signaling pathway mediates developmental processes and the proper functioning of the adult human body. This distinctive bidirectional signaling pathway includes a canonical downstream signal cascade inside the Eph-bearing cells, as well as a reverse signaling in the ephrin-bearing cells. The signaling is terminated by ADAM metalloproteinase cleavage, internalization, and degradation of the Eph/ephrin complexes. Consequently, the Eph-ephrin-ADAM signaling cascade has emerged as a key target with immense therapeutic potential particularly in the context of cancer. An interesting twist was brought forth by the emergence of ephrins as the entry receptors for the pathological Henipaviruses, which has spurred new studies to target the viral entry. The availability of high-resolution structures of the multi-modular Eph receptors in complexes with ephrins and other binding partners, such as peptides, small molecule inhibitors and antibodies, offers a wealth of information for the structure-guided development of therapeutic intervention. Furthermore, genomic data mining of Eph mutants involved in cancer provides information for targeted drug development. In this review we summarize the distinct avenues for targeting the Eph-ephrin signaling pathway, including its termination by ADAM proteinases. We highlight the latest developments in Eph-related pharmacology in the context of Eph-ephrin-ADAM-based antibodies and small molecules. Finally, the future prospects of genomics- and proteomics-based medicine are discussed.

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Exploring the Ability of Cyclic Peptides to Target SAM Domains: A Computational and Experimental Study

et al. 2019

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Sterile alpha motif (SAM) domains are protein interaction modules with a helical fold. SAM–SAM interactions often adopt the mid‐loop (ML)/end‐helix (EH) model, in which the C‐terminal helix and adjacent loops of one SAM unit (EH site) bind the central regions of another SAM domain (ML site). Herein, an original strategy to attack SAM–SAM associations is reported. It relies on the design of cyclic peptides that target a region of the SAM domain positioned at the bottom side of the EH interface, which is thought to be important for the formation of a SAM–SAM complex. This strategy has been preliminarily tested by using a model system of heterotypic SAM–SAM interactions involving the erythropoietin‐producing hepatoma kinase A2 (EphA2) receptor and implementing a multidisciplinary plan made up of computational docking studies, experimental interaction assays (by NMR spectroscopy and surface plasmon resonance techniques) and conformational analysis (by NMR spectroscopy and circular dichroism). This work further highlights how only a specific balance between flexibility and rigidity may be needed to generate modulators of SAM–SAM interactions.

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A role of the SAM domain in EphA2 receptor activation

Cited by 42 publications

References 47 publications

Eph receptor signalling: from catalytic to non-catalytic functions

Eph receptor signalling: from catalytic to non-catalytic functions

Therapeutic potential of targeting the Eph/ephrin signaling complex

Exploring the Ability of Cyclic Peptides to Target SAM Domains: A Computational and Experimental Study

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