Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK
| Autor: | Edward J. Natoli, Gwenda F. Ligon, Xiarong Shi, Irit Lax, Ewa Folta-Stogniew, Joseph Schlessinger, Andrey V. Reshetnyak, Jay S. Lillquist, Diego Alvarado, Murat Gunel, Phillip B. Murray |
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| Rok vydání: | 2015 |
| Předmět: |
Blotting
Western Ligands Receptor Tyrosine Kinase-like Orphan Receptors Biochemistry Receptor tyrosine kinase hemic and lymphatic diseases Neuroblastoma medicine Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Phosphorylation Receptor Molecular Biology Orphan receptor biology Heparin Chemistry Receptor Protein-Tyrosine Kinases Cell Biology medicine.disease Molecular biology Protein Structure Tertiary Enzyme Activation biology.protein Cancer research Dimerization Tyrosine kinase Protein Binding Signal Transduction medicine.drug |
| Zdroj: | Science Signaling. 8 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.2005916 |
| Popis: | Anaplastic lymphoma kinase (ALK) is one of the few remaining "orphan" receptor tyrosine kinases (RTKs) in which the ligands are unknown. Ligand-mediated activation of RTKs is important throughout development. ALK is particularly relevant to the development of the nervous system. Increased activation of RTKs by mutation, genetic amplification, or signals from the stroma contributes to disease progression and acquired drug resistance in cancer. Aberrant activation of ALK occurs in subsets of lung adenocarcinoma, neuroblastoma, and other cancers. We found that heparin is a ligand that binds specifically to the ALK extracellular domain. Whereas heparins with short chain lengths bound to ALK in a monovalent manner and did not activate the receptor, longer heparin chains induced ALK dimerization and activation in cultured neuroblastoma cells. Heparin lacking N- and O-linked sulfate groups or other glycosaminoglycans with sulfation patterns different than heparin failed to activate ALK. Moreover, antibodies that bound to the extracellular domain of ALK interfered with heparin binding and prevented heparin-mediated activation of ALK. Thus, heparin and perhaps related glycosaminoglycans function as ligands for ALK, revealing a potential mechanism for the regulation of ALK activity in vivo and suggesting an approach for developing ALK-targeted therapies for cancer. |
| Databáze: | OpenAIRE |
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