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The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling

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The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling. / Dzamko, N.; Inesta-Vaquera, F.; Zhang, J.; Arthur, S.; Cohen, P.; Clark, K.; Alessi, D.R.; Xie, C.; Cai, H.; Tan, L.; Choi, H.; Gray, N.; Pedrioli, P.

In: PLoS ONE, Vol. 7, No. 6, e39132, 2012.

Research output: Contribution to journalArticle

Harvard

Dzamko, N, Inesta-Vaquera, F, Zhang, J, Arthur, S, Cohen, P, Clark, K, Alessi, DR, Xie, C, Cai, H, Tan, L, Choi, H, Gray, N & Pedrioli, P 2012, 'The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling' PLoS ONE, vol 7, no. 6, e39132.

APA

Dzamko, N., Inesta-Vaquera, F., Zhang, J., Arthur, S., Cohen, P., Clark, K., Alessi, D. R., Xie, C., Cai, H., Tan, L., Choi, H., Gray, N., & Pedrioli, P. (2012). The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling. PLoS ONE, 7(6), [e39132]doi: 10.1371/journal.pone.0039132

Vancouver

Dzamko N, Inesta-Vaquera F, Zhang J, Arthur S, Cohen P, Clark K et al. The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling. PLoS ONE. 2012;7(6). e39132.

Author

Dzamko, N.; Inesta-Vaquera, F.; Zhang, J.; Arthur, S.; Cohen, P.; Clark, K.; Alessi, D.R.; Xie, C.; Cai, H.; Tan, L.; Choi, H.; Gray, N.; Pedrioli, P. / The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling.

In: PLoS ONE, Vol. 7, No. 6, e39132, 2012.

Research output: Contribution to journalArticle

Bibtex - Download

@article{3e0ec8d0f8be4c959d87b4ae45874712,
title = "The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling",
author = "N. Dzamko and F. Inesta-Vaquera and J. Zhang and S. Arthur and P. Cohen and K. Clark and D.R. Alessi and C. Xie and H. Cai and L. Tan and H. Choi and N. Gray and P. Pedrioli",
year = "2012",
volume = "7",
number = "6",
journal = "PLoS ONE",
issn = "1932-6203",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor signaling

A1 - Dzamko,N.

A1 - Inesta-Vaquera,F.

A1 - Zhang,J.

A1 - Arthur,S.

A1 - Cohen,P.

A1 - Clark,K.

A1 - Alessi,D.R.

A1 - Xie,C.

A1 - Cai,H.

A1 - Tan,L.

A1 - Choi,H.

A1 - Gray,N.

A1 - Pedrioli,P.

AU - Dzamko,N.

AU - Inesta-Vaquera,F.

AU - Zhang,J.

AU - Arthur,S.

AU - Cohen,P.

AU - Clark,K.

AU - Alessi,D.R.

AU - Xie,C.

AU - Cai,H.

AU - Tan,L.

AU - Choi,H.

AU - Gray,N.

AU - Pedrioli,P.

PY - 2012

Y1 - 2012

N2 - Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. LRRK2 is highly expressed in immune cells and recent work points towards a link between LRRK2 and innate immunity. Here we demonstrate that stimulation of the Toll-Like Receptor (TLR) pathway by MyD88-dependent agonists in bone marrow-derived macrophages (BMDMs) or RAW264.7 macrophages induces marked phosphorylation of LRRK2 at Ser910 and Ser935, the phosphorylation sites that regulate the binding of 14-3-3 to LRRK2. Phosphorylation of these residues is prevented by knock-out of MyD88 in BMDMs, but not the alternative TLR adaptor protein TRIF. Utilising both pharmacological inhibitors, including a new TAK1 inhibitor, NG25, and genetic models, we provide evidence that both the canonical (IKKa and IKKß) and IKK-related (IKKe and TBK1) kinases mediate TLR agonist induced phosphorylation of LRRK2 in vivo. Moreover, all four IKK members directly phosphorylate LRRK2 at Ser910 and Ser935 in vitro. Consistent with previous work describing Ser910 and Ser935 as pharmacodynamic biomarkers of LRRK2 activity, we find that the TLR independent basal phosphorylation of LRRK2 at Ser910 and Ser935 is abolished following treatment of macrophages with LRRK2 kinase inhibitors. However, the increased phosphorylation of Ser910 and Ser935 induced by activation of the MyD88 pathway is insensitive to LRRK2 kinase inhibitors. Finally, employing LRRK2-deficient BMDMs, we present data indicating that LRRK2 does not play a major role in regulating the secretion of inflammatory cytokines induced by activation of the MyD88 pathway. Our findings provide the first direct link between LRRK2 and the IKKs that mediate many immune responses. Further work is required to uncover the physiological roles that phosphorylation of LRRK2 by IKKs play in controlling macrophage biology and to determine how phosphorylation of LRRK2 by IKKs impacts upon the use of Ser910 and Ser935 as pharmacodynamic biomarkers.

AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. LRRK2 is highly expressed in immune cells and recent work points towards a link between LRRK2 and innate immunity. Here we demonstrate that stimulation of the Toll-Like Receptor (TLR) pathway by MyD88-dependent agonists in bone marrow-derived macrophages (BMDMs) or RAW264.7 macrophages induces marked phosphorylation of LRRK2 at Ser910 and Ser935, the phosphorylation sites that regulate the binding of 14-3-3 to LRRK2. Phosphorylation of these residues is prevented by knock-out of MyD88 in BMDMs, but not the alternative TLR adaptor protein TRIF. Utilising both pharmacological inhibitors, including a new TAK1 inhibitor, NG25, and genetic models, we provide evidence that both the canonical (IKKa and IKKß) and IKK-related (IKKe and TBK1) kinases mediate TLR agonist induced phosphorylation of LRRK2 in vivo. Moreover, all four IKK members directly phosphorylate LRRK2 at Ser910 and Ser935 in vitro. Consistent with previous work describing Ser910 and Ser935 as pharmacodynamic biomarkers of LRRK2 activity, we find that the TLR independent basal phosphorylation of LRRK2 at Ser910 and Ser935 is abolished following treatment of macrophages with LRRK2 kinase inhibitors. However, the increased phosphorylation of Ser910 and Ser935 induced by activation of the MyD88 pathway is insensitive to LRRK2 kinase inhibitors. Finally, employing LRRK2-deficient BMDMs, we present data indicating that LRRK2 does not play a major role in regulating the secretion of inflammatory cytokines induced by activation of the MyD88 pathway. Our findings provide the first direct link between LRRK2 and the IKKs that mediate many immune responses. Further work is required to uncover the physiological roles that phosphorylation of LRRK2 by IKKs play in controlling macrophage biology and to determine how phosphorylation of LRRK2 by IKKs impacts upon the use of Ser910 and Ser935 as pharmacodynamic biomarkers.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84862497413&md5=de9ab07eec18e5a3e7fadc881dcae058

U2 - 10.1371/journal.pone.0039132

DO - 10.1371/journal.pone.0039132

M1 - Article

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 6

VL - 7

ER -

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