2c5d

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Template:STRUCTURE 2c5d

Contents 1 STRUCTURE OF A MINIMAL GAS6-AXL COMPLEX 2 Disease 3 Function 4 About this Structure 5 Reference

STRUCTURE OF A MINIMAL GAS6-AXL COMPLEX

Template:ABSTRACT PUBMED 16362042

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

[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.^{[1][2][3][4][5][6][7][8][9]}

About this Structure

2c5d is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

• Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R, Hohenester E. Structural basis for Gas6-Axl signalling. EMBO J. 2006 Jan 11;25(1):80-7. Epub 2005 Dec 15. PMID:16362042
• Sasaki T, Knyazev PG, Cheburkin Y, Gohring W, Tisi D, Ullrich A, Timpl R, Hohenester E. Crystal structure of a C-terminal fragment of growth arrest-specific protein Gas6. Receptor tyrosine kinase activation by laminin G-like domains. J Biol Chem. 2002 Nov 15;277(46):44164-70. Epub 2002 Sep 5. PMID:12218057 doi:10.1074/jbc.M207340200
• Heiring C, Dahlback B, Muller YA. Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family. J Biol Chem. 2004 Feb 20;279(8):6952-8. Epub 2003 Nov 17. PMID:14623883 doi:10.1074/jbc.M311750200

1. ↑ O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991 Oct;11(10):5016-31. PMID:1656220
2. ↑ Jacob AN, Kalapurakal J, Davidson WR, Kandpal G, Dunson N, Prashar Y, Kandpal RP. A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145. Cancer Detect Prev. 1999;23(4):325-32. PMID:10403904
3. ↑ Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC. Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. Ann Oncol. 2001 Jun;12(6):819-24. PMID:11484958
4. ↑ D'Arcangelo D, Gaetano C, Capogrossi MC. Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res. 2002 Oct 4;91(7):e4-12. PMID:12364394
5. ↑ Ito M, Nakashima M, Nakayama T, Ohtsuru A, Nagayama Y, Takamura N, Demedchik EP, Sekine I, Yamashita S. Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl. Thyroid. 2002 Nov;12(11):971-5. PMID:12490074 doi:10.1089/105072502320908303
6. ↑ Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, Avanzi GC, Bussolino F. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood. 2005 Mar 1;105(5):1970-6. Epub 2004 Oct 26. PMID:15507525 doi:10.1182/blood-2004-04-1469
7. ↑ Gould WR, Baxi SM, Schroeder R, Peng YW, Leadley RJ, Peterson JT, Perrin LA. Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J Thromb Haemost. 2005 Apr;3(4):733-41. Epub 2005 Feb 23. PMID:15733062 doi:10.1111/j.1538-7836.2005.01186.x
8. ↑ Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Oct;80(20):10109-16. PMID:17005688 doi:80/20/10109
9. ↑ Park IK, Giovenzana C, Hughes TL, Yu J, Trotta R, Caligiuri MA. The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood. 2009 Mar 12;113(11):2470-7. doi: 10.1182/blood-2008-05-157073. Epub 2008, Oct 7. PMID:18840707 doi:10.1182/blood-2008-05-157073