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(New page: ==High-affinity AXL decoy receptor== <StructureSection load='5vxz' size='340' side='right' caption='5vxz, resolution 2.30Å' scene=''> == Structural highlights == ...)
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Revision as of 09:06, 16 November 2017
proteopedia linkproteopedia linkHigh-affinity AXL decoy receptor
Structural highlights
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.[1] [2] [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.[3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedThe AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers gammaH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies.,Kariolis MS, Miao YR, Diep A, Nash SE, Olcina MM, Jiang D, Jones DS 2nd, Kapur S, Mathews II, Koong AC, Rankin EB, Cochran JR, Giaccia AJ J Clin Invest. 2017 Jan 3;127(1):183-198. doi: 10.1172/JCI85610. Epub 2016 Nov, 28. PMID:27893463[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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