Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673).
In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150).
Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166).
MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150).
May function as regulator of gastric epithelial differentiation (By similarity)
Homodimer; homodimerizes following heparin- and ligand-binding (PubMed:16317043, PubMed:25605972, PubMed:34646012, PubMed:34819673). Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:15226403, PubMed:16878150, PubMed:17274988).
Interacts with PTN and MDK (PubMed:11278720, PubMed:12122009)
Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells
The EGF-like region drives the cytokine specificity for ALKAL2
The heparin-binding region binds heparin glycosaminoglycan (PubMed:25605972, PubMed:34646012). Heparin-binding is required for ALKAL2-driven activation (PubMed:34646012)
A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.
Click a pathway to open the interactive Reactome viewer.
Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to ALKBH1, aggregated across our SSL data sources. Click any partner node to view that gene’s page.
Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.
Total Trials Found: 41
| NCT ID | Condition | Brief Title | Phase | Status |
|---|---|---|---|---|
| NCT03213652 | Advanced Malignant Solid Neoplasm, Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Wilms Tumor | Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial) | PHASE2 | ACTIVE_NOT_RECRUITING |
| NCT04087473 | Non-small Cell Lung Cancer, ALK-Positive Lung Cancer | Plasma Molecular Profiling in ALK Inhibitor Resistant NSCLC | N/A | RECRUITING |
| NCT04427072 | Carcinoma, Non-Small-Cell Lung | Study of Capmatinib Efficacy in Comparison With Docetaxel in Previously Treated Participants With Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation | PHASE3 | TERMINATED |
| NCT04800822 | Solid Tumor | PF-07284892 in Participants With Advanced Solid Tumors | PHASE1 | TERMINATED |
| NCT02227940 | Advanced Malignant Solid Neoplasm, ALK Positive, Metastatic Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer | Ceritinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic Pancreatic Cancer | PHASE1 | COMPLETED |
| NCT04094610 | Locally Advanced Solid Tumors, Metastatic Solid Tumors, Lymphoma, Primary CNS Tumors | A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations | PHASE1, PHASE2 | RECRUITING |
| NCT04127110 | Non Small Cell Lung Cancer | Activity of Lorlatinib Based on ALK Resistance Mutations Detected on Blood in ALK Positive NSCLC Patients | PHASE2 | ACTIVE_NOT_RECRUITING |
| NCT04681131 | Non-Small-Cell Lung Cancer | CAB-AXL-ADC Safety and Efficacy Study in Adults With NSCLC | PHASE2 | COMPLETED |
| NCT02927340 | Non-Small Cell Lung Cancer (NSCLC) | A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions | PHASE2 | UNKNOWN |
| NCT03564197 | NSCLC Stage IV | 18F-PD-L1 PET/CT in Nivolumab Treated Patients With NSCLC | NA | COMPLETED |