4ra0

An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis

spinqualitylabelsall models 4ra0, resolution 3.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ra0 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, CL, NI, SO4, NAG Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, RCSB, PDBsum Disease [UFO_HUMAN] Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer. Function [GAS6_HUMAN] Ligand for tyrosine-protein kinase receptors AXL, TYRO3 and MER whose signaling is implicated in cell growth and survival, cell adhesion and cell migration. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. [UFO_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TENC1. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. In case of filovirus infection, seems to function as a cell entry factor. Publication Abstract from PubMed Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo. An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis.,Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews II, Giaccia AJ, Cochran JR Nat Chem Biol. 2014 Nov;10(11):977-83. doi: 10.1038/nchembio.1636. Epub 2014 Sep , 21. PMID:25242553 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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