Activation of the orphan receptor tyrosine kinase ALK by zinc.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed during development of the central and peripheral nervous system. The nature of the cognate ligand of this receptor in Vertebrates is still a matter of debate. During synaptic transmission the release of ionic zinc found in vesicles of certain glutamatergic and gabaergic terminals may act as a neuromodulator by binding to pre- or post-synaptic receptors. Recently, zinc has been shown to activate the receptor tyrosine kinase, TrkB, independently of neurotrophins. This activation occurs via increasing the Src family kinase activity. In the present study, we investigated whether the ALK activity could be modulated by extracellular zinc. We first showed that zinc alone rapidly activates ALK. This activation is dependent of ALK tyrosine kinase activity and dimerization of the receptor but is independent of Src family kinase activity. In contrast, addition of sodium pyrithione, a zinc ionophore, led to a further activation of ALK. This stronger activation is dependent of Src family kinase but independent of ALK activity and dimerization. In conclusion, zinc could constitute an endogenous ligand of ALK in vertebrates.
Bennasroune
Aline
A
UMR_S839 INSERM/UPMC, Institut du Fer à Moulin (IFM), 17 rue du Fer à Moulin, 75005 Paris, France.
Mazot
Pierre
P
Boutterin
Marie-Claude
MC
Vigny
Marc
M
D000077548:Anaplastic Lymphoma Kinase; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D013871:Thiones / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D011725:Pyridines; D013871:Thiones; C008704:pyrithione; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases; D015032:Zinc