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Chem Biol DOI:10.1016/j.chembiol.2011.03.017

AAK1 identified as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics.

Publication TypeJournal Article
Year of Publication2011
AuthorsKuai, L, Ong, S-E, Madison, JM, Wang, X, Duvall, JR, Lewis, TA, Luce, CJ, Conner, SD, Pearlman, DA, Wood, JL, Schreiber, SL, Carr, SA, Scolnick, EM, Haggarty, SJ
JournalChem Biol
Volume18
Issue7
Pages891-906
Date Published2011 Jul 29
ISSN1879-1301
KeywordsAnimals, Carbazoles, Gene Knockdown Techniques, Genomics, Humans, Indole Alkaloids, Models, Molecular, Nerve Growth Factors, Neuregulin-1, Neurites, PC12 Cells, Protein-Serine-Threonine Kinases, Proteomics, Rats, Receptor, Epidermal Growth Factor, Receptor, ErbB-4, Signal Transduction
Abstract

Target identification remains challenging for the field of chemical biology. We describe an integrative chemical genomic and proteomic approach combining the use of differentially active analogs of small molecule probes with stable isotope labeling by amino acids in cell culture-mediated affinity enrichment, followed by subsequent testing of candidate targets using RNA interference-mediated gene silencing. We applied this approach to characterizing the natural product K252a and its ability to potentiate neuregulin-1 (Nrg1)/ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4)-dependent neurotrophic factor signaling and neuritogenesis. We show that AAK1 (adaptor-associated kinase 1) is a relevant target of K252a, and that the loss of AAK1 alters ErbB4 trafficking and expression levels, providing evidence for a previously unrecognized role for AAK1 in Nrg1-mediated neurotrophic factor signaling. Similar strategies should lead to the discovery of novel targets for therapeutic development.

DOI10.1016/j.chembiol.2011.03.017
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21802010?dopt=Abstract

Alternate JournalChem. Biol.
PubMed ID21802010
PubMed Central IDPMC3368601
Grant ListUL1RR024924 / RR / NCRR NIH HHS / United States
R01 MH095088-01 / MH / NIMH NIH HHS / United States
R21 MH087896 / MH / NIMH NIH HHS / United States
R21 MH087896-02 / MH / NIMH NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
R33 MH087896 / MH / NIMH NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
1R21MH087896-01 / MH / NIMH NIH HHS / United States
RL1 HG004671-05 / HG / NHGRI NIH HHS / United States
UL1 RR024924 / RR / NCRR NIH HHS / United States
R33 MH087896-03 / MH / NIMH NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
N01 CO012400 / CO / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
R21 MH087896-01 / MH / NIMH NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
R01 MH095088 / MH / NIMH NIH HHS / United States