AXL

Synonyms

AXL Oncogene, EC 2.7.10.1, JTK11, Tyro7, ARK, Tyrosine-protein kinase receptor UFO, AXL, AXL Receptor Tyrosine Kinase, EC 2.7.10, EC:2.7.10.1, UFO, AXL Transforming Sequence/Gene

Description

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 TNS2. 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.(Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope.(Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope.

KO Status

RenMab: F0

Drug Information

Launched drugs: 2
Drugs in clinical trials: 18
Latest Research Phase: Approved

Drug Name

Code

Phase

Company

Indications

Clinical Trials

Gilteritinib Fumarate

ASP-2215 hemifumarate, ASP-2215, 66D-92MGC8M (UNII code)

Approved

Astellas Pharma Inc

Solid tumours, Renal Insufficiency, Hepatic Insufficiency, Leukemia, Myeloid, Acute

Cabozantinib S-malate

BMS-907351, XL-184

Approved

Exelixis Inc

Solid tumours, Pain, Stomach Neoplasms, Carcinoma, Renal Cell, Esophageal Neoplasms, Glioblastoma, Kidney Diseases, Prostatic Neoplasms, Colorectal Neoplasms, Astrocytoma, Hepatic Insufficiency, Thyroid Neoplasms, Carcinoma, Neuroendocrine, Lymphoma, Carcinoma, Non-Small-Cell Lung, Carcinoma, Hepatocellular

ONO-7475

ONO-7475

Phase 2 Clinical

Ono Pharmaceutical Co Ltd

Leukemia, Myelodysplastic Syndromes, Neoplasms, Leukemia, Myeloid, Acute

S-49076

S-49076

Phase 2 Clinical

Servier

Glioblastoma, Carcinoma, Non-Small-Cell Lung

Butylidenephthalide

BDPH, HK-001, NSC-325307

Phase 2 Clinical

Everfront Biotech Co Ltd

Glioma, Amyotrophic Lateral Sclerosis

Bemcentinib

R-428, BGB-324

Phase 2 Clinical

Rigel Pharmaceuticals Inc

Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Non-alcoholic Fatty Liver Disease, Coronavirus Disease 2019 (COVID-19), Inflammatory Breast Neoplasms, Triple Negative Breast Neoplasms, Pancreatic Neoplasms, Idiopathic Pulmonary Fibrosis, Myelodysplastic Syndromes, Adenocarcinoma of Lung, Breast Neoplasms, Leukemia, Myeloid, Acute, Lung Neoplasms, Melanoma, Carcinoma, Non-Small-Cell Lung

Ningetinib Tosylate

CT-053, CT-053-PTSA

Phase 2 Clinical

Hec Pharm Co Ltd

Solid tumours, Intestinal Neoplasms, Stomach Neoplasms, Carcinoma, Renal Cell, Leukemia, Myeloid, Acute, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Carcinoma, Hepatocellular

BA-3011

BA-3011

Phase 2 Clinical

Bioatla

Leiomyosarcoma, Solid tumours, Pancreatic Neoplasms, Liposarcoma, Sarcoma, Synovial, Osteosarcoma, Sarcoma, Ewing, Sarcoma, Melanoma, Carcinoma, Non-Small-Cell Lung

Enapotamab vedotin (Genmab)

AXL-107-MMAE

Phase 2 Clinical

Seattle Genetics Inc, Genmab

Ovarian Neoplasms, Sarcoma, Endometrial Neoplasms, Thyroid Neoplasms, Carcinoma, Non-Small-Cell Lung, Uterine Cervical Neoplasms, Melanoma

Dubermatinib

TP-0903

Phase 2 Clinical

Sumitomo Dainippon

Ovarian Neoplasms, Colorectal Neoplasms, Leukemia, Lymphocytic, Chronic, B-Cell, Melanoma, Carcinoma, Non-Small-Cell Lung

References


Title

Authors

Source

Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor

Gallicchio M., Mitola S., Valdembri D., Fantozzi R., Varnum B., Avanzi G.C., Bussolino F.,

Blood 105:1970-1976(2005)

Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses

Gould W.R., Baxi S.M., Schroeder R., Peng Y.W., Leadley R.J., Peterson J.T., Perrin L.A.,

J. Thromb. Haemost. 3:733-741(2005)

Tyro3 family-mediated cell entry of Ebola and Marburg viruses

Shimojima M., Takada A., Ebihara H., Neumann G., Fujioka K., Irimura T., Jones S., Feldmann H., Kawaoka Y.,

J. Virol. 80:10109-10116(2006)

In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation

Weinger J.G., Gohari P., Yan Y., Backer J.M., Varnum B., Shafit-Zagardo B.,

J. Neurochem. 106:134-146(2008)

Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle

Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.,

Mol. Cell 31:438-448(2008)

The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development

Park I.K., Giovenzana C., Hughes T.L., Yu J., Trotta R., Caligiuri M.A.,

Blood 113:2470-2477(2009)

Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling

Pao-Chun L., Chan P.M., Chan W., Manser E.,

J. Biol. Chem. 284:34954-34963(2009)

The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry

Morizono K., Xie Y., Olafsen T., Lee B., Dasgupta A., Wu A.M., Chen I.S.,

Cell Host Microbe 9:286-298(2011)

Identification of cell surface molecules involved in dystroglycan-independent Lassa virus cell entry

Shimojima M., Stroher U., Ebihara H., Feldmann H., Kawaoka Y.,

J. Virol. 86:2067-2078(2012)

Cell surface molecules involved in infection mediated by lymphocytic choriomeningitis virus glycoprotein

Shimojima M., Kawaoka Y.,

J. Vet. Med. Sci. 74:1363-1366(2012)