Research article summary (published 29 Sep 2009):

Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation.

Full Abstract

DYRK1A is a dual-specificity protein kinase that autophosphorylates a conserved tyrosine residue in the activation loop but phosphorylates exogenous substrates only at serine or threonine residues. Tyrosine autophosphorylation of DYRKs is a one-off event that takes place during translation and induces the activation of the kinase. Here we characterize the beta-carboline alkaloid harmine as a potent and specific inhibitor of DYRK1A both in vitro and in cultured cells. Comparative in vitro assays of four kinases of the DYRK family showed that harmine inhibited substrate phosphorylation by DYRK1A more potently than it inhibited substrate phosphorylation by the closely related kinase DYRK1B [half maximal inhibitory concentrations (IC(50)) of 33 nm versus 166 nm, respectively] and by the more distant members of the family, DYRK2 and DYRK4 (1.9 microm and 80 microm, respectively). Much higher concentrations of harmine were required to suppress tyrosine autophosphorylation of the translational intermediate of DYRK1A in a bacterial in vitro translation system (IC(50) = 1.9 microm). Importantly, harmine inhibited the phosphorylation of a specific substrate by DYRK1A in cultured cells with a potency similar to that observed in vitro (IC(50) = 48 nm), without negative effects on the viability of the cells. Overexpression of the DYRK1A gene on chromosome 21 has been implicated in the altered neuronal development observed in Down syndrome. Here, we show that harmine interferes with neuritogenesis in cultured hippocampal neurons. In summary, our data show that harmine inhibits DYRK1A substrate phosphorylation more potently than it inhibits tyrosine autophosphorylation, and provide evidence for a role of DYRK1A in the regulation of neurite formation.

Author information

Author/s: Göckler, Nora (N); Jofre, Guillermo (G); Papadopoulos, Chrisovalantis (C); Soppa, Ulf (U); Tejedor, Francisco J (FJ); Becker, Walter (W);

Affiliation: Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The FEBS journal (FEBS J), published in England. (Language: eng)

Reference: 2009-Nov; vol 276 (issue 21) : pp 6324-37

Dates: Created 2009/10/14; Completed 2009/10/28;

PMID: 19796173, status: MEDLINE (last retrieval date: 10/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Cells, Cultured Harmine - pharmacology Hela Cells Hippocampus - drug effects Humans Mice

Neurites - drug effects; physiology Phosphorylation Protein Biosynthesis - drug effects Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - antagonists & inhibitors Tyrosine - metabolism

Associated Chemicals: Protein Kinase Inhibitors (0) ; Harmine (442-51-3) ; Tyrosine (55520-40-6) ; Dyrk kinase (EC 2.7.1.-) ; Protein-Tyrosine Kinases (EC 2.7.1.112) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)

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