Research ArticleCell Biology

Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK

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Science Signaling  20 Jan 2015:
Vol. 8, Issue 360, pp. ra6
DOI: 10.1126/scisignal.2005916

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De-Orphaning ALK

Receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), are important during development and regeneration and are often aberrantly activated in cancer. ALK is an orphan RTK with no known ligand. Murray et al. found that heparin bound directly and with high affinity to a specific region in the extracellular domain of ALK. Heparin stimulated ALK activation and signaling in NB1 cells through a mechanism that required heparin sulfation and the ability of heparin to promote dimerization of ALK. Moreover, an antibody that competed with heparin for binding to ALK prevented heparin-mediated activation of ALK. These results define heparin as an ALK-binding agonist, thereby providing potential avenues for therapeutic intervention.

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