title: Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Murray
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Lax
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Reshetnyak
authors.affiliation: Kolltan Pharmaceuticals, New Haven, CT 06520, USA.
authors.forename: Gwenda F
authors.initials: GF
authors.lastname: Ligon
authors.affiliation: Kolltan Pharmaceuticals, New Haven, CT 06520, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Lillquist
authors.affiliation: Kolltan Pharmaceuticals, New Haven, CT 06520, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Natoli
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiarong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, CT 06520, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Folta-Stogniew
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Kolltan Pharmaceuticals, New Haven, CT 06520, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarado
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. joseph.schlessinger@yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D015153:Blotting, Western; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008024:Ligands; D006493:Heparin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors