Axl-dependent Signalling: a Clinical Update

Overview

Journal Clin Sci (Lond)

Specialties Biochemistry
General Medicine
Science

Date 2011 Dec 23

PMID 22187964

Citations 84

Authors

Vyacheslav A Korshunov

Affiliations

Soon will be listed here.

Abstract

Axl is a receptor tyrosine kinase that was originally cloned from cancer cells. Axl belongs to the TAM (Tyro3, Axl and Mertk) family of receptor tyrosine kinases. Gas6 (growth-arrest-specific protein 6) is a ligand for Axl. Activation of Axl protects cells from apoptosis, and increases migration, aggregation and growth through multiple downstream pathways. Up-regulation of the Gas6/Axl pathway is more evident in pathological conditions compared with normal physiology. Recent advances in Axl receptor biology are summarized in the present review. The emphasis is given to translational aspects of Axl-dependent signalling under pathological conditions. In particular, inhibition of Axl reduces tumorigenesis and prevents metastasis as well. Axl-dependent signals are important for the progression of cardiovascular diseases. In contrast, deficiency of Axl in innate immune cells contributes to the pathogenesis of autoimmune disorders. Current challenges in Axl biology are related to the functional interactions of Axl with other members of the TAM family or other tyrosine kinases, mechanisms of ligand-independent activation, inactivation of the receptor and cell-cell interactions (with respect to immune cells) in chronic diseases.

Citing Articles

AXL signaling in cancer: from molecular insights to targeted therapies.

Yadav M, Sharma A, Patne K, Tabasum S, Suryavanshi J, Rawat L Signal Transduct Target Ther. 2025; 10(1):37.

PMID: 39924521 PMC: 11808115. DOI: 10.1038/s41392-024-02121-7.

Orderly Regulation of Macrophages and Fibroblasts by Axl in Bleomycin-Induced Pulmonary Fibrosis in Mice.

Zhao X, Li Y, Yang S, Chen Y, Wu K, Geng J J Cell Mol Med. 2025; 29(1):e70321.

PMID: 39779468 PMC: 11710931. DOI: 10.1111/jcmm.70321.

NF-κB: Governing Macrophages in Cancer.

Cornice J, Verzella D, Arboretto P, Vecchiotti D, Capece D, Zazzeroni F Genes (Basel). 2024; 15(2).

PMID: 38397187 PMC: 10888451. DOI: 10.3390/genes15020197.

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment.

Frumento D, Grossi G, Falesiedi M, Musumeci F, Carbone A, Schenone S Int J Mol Sci. 2024; 25(3).

PMID: 38338677 PMC: 10855061. DOI: 10.3390/ijms25031398.

Ethyl pyruvate attenuates cerebral hypoxia/reoxygenation injury in neuroblastoma cells: Role of GAS6/Axl signaling.

Chen Y, Chen J, Zhao L, Zhang X, Wu X, Wang X Heliyon. 2023; 9(12):e22787.

PMID: 38090008 PMC: 10711176. DOI: 10.1016/j.heliyon.2023.e22787.

References

Burchert A, Attar E, MCCLOSKEY P, Fridell Y, Liu E . Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene. 1998; 16(24):3177-87. DOI: 10.1038/sj.onc.1201865. View

Thorp E, Vaisar T, Subramanian M, Mautner L, Blobel C, Tabas I . Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK). J Biol Chem. 2011; 286(38):33335-44. PMC: 3190938. DOI: 10.1074/jbc.M111.263020. View

Berk B . Vascular smooth muscle growth: autocrine growth mechanisms. Physiol Rev. 2001; 81(3):999-1030. DOI: 10.1152/physrev.2001.81.3.999. View

Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H . Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem. 1996; 271(47):30022-7. DOI: 10.1074/jbc.271.47.30022. View

Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, Avanzi G . Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood. 2004; 105(5):1970-6. DOI: 10.1182/blood-2004-04-1469. View

Sharif M, Sosic D, Rothlin C, Kelly E, Lemke G, Olson E . Twist mediates suppression of inflammation by type I IFNs and Axl. J Exp Med. 2006; 203(8):1891-901. PMC: 2118370. DOI: 10.1084/jem.20051725. View

Hurtado B, Abasolo N, Munoz X, Garcia N, Benavente Y, Rubio F . Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis. Thromb Haemost. 2010; 104(3):592-8. DOI: 10.1160/TH09-11-0787. View

Melaragno M, Wuthrich D, Poppa V, Gill D, Lindner V, Berk B . Increased expression of Axl tyrosine kinase after vascular injury and regulation by G protein-coupled receptor agonists in rats. Circ Res. 1998; 83(7):697-704. DOI: 10.1161/01.res.83.7.697. View

Smolock E, Korshunov V . Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress. Vascul Pharmacol. 2010; 53(3-4):185-92. DOI: 10.1016/j.vph.2010.07.002. View

10.

Tjwa M, Bellido-Martin L, Lin Y, Lutgens E, Plaisance S, Bono F . Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes. Blood. 2007; 111(8):4096-105. DOI: 10.1182/blood-2007-05-089565. View

11.

Meric F, Lee W, Sahin A, Zhang H, Kung H, Hung M . Expression profile of tyrosine kinases in breast cancer. Clin Cancer Res. 2002; 8(2):361-7. View

12.

Cavet M, Smolock E, Ozturk O, World C, Pang J, Konishi A . Gas6-axl receptor signaling is regulated by glucose in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2008; 28(5):886-91. PMC: 2731942. DOI: 10.1161/ATVBAHA.108.162693. View

13.

Korshunov V, Mohan A, Georger M, Berk B . Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling. Circ Res. 2006; 98(11):1446-52. DOI: 10.1161/01.RES.0000223322.16149.9a. View

14.

Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T . Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010; 107(3):1124-9. PMC: 2824310. DOI: 10.1073/pnas.0909333107. View

15.

Lu Q, Lemke G . Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001; 293(5528):306-11. DOI: 10.1126/science.1061663. View

16.

Ghosh A, Secreto C, Boysen J, Sassoon T, Shanafelt T, Mukhopadhyay D . The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood. 2010; 117(6):1928-37. PMC: 3056640. DOI: 10.1182/blood-2010-09-305649. View

17.

Hafizi S, Ibraimi F, Dahlback B . C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. FASEB J. 2005; 19(8):971-3. DOI: 10.1096/fj.04-2532fje. View

18.

Lemke G, Rothlin C . Immunobiology of the TAM receptors. Nat Rev Immunol. 2008; 8(5):327-36. PMC: 2856445. DOI: 10.1038/nri2303. View

19.

Scott R, McMahon E, Pop S, Reap E, Caricchio R, Cohen P . Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001; 411(6834):207-11. DOI: 10.1038/35075603. View

20.

Linger R, Keating A, Earp H, Graham D . TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008; 100:35-83. PMC: 3133732. DOI: 10.1016/S0065-230X(08)00002-X. View