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PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

Berndsen, Kerryn, Lis, Pawel, Yeshaw, Wondwossen M, Wawro, Paulina S, Nirujogi, Raja S, Wightman, Melanie, Macartney, Thomas, Dorward, Mark, Knebel, Axel, Tonelli, Francesca, Pfeffer, Suzanne R, Alessi, Dario R·2019·eLife
DOI 10.7554/elife.50416PMC PMC6850886

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Abstract

Mutations that activate LRRK2 protein kinase cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knockout increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation in human A549 cells. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A “substrate-trapping” PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson’s disease.

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Metadata

Authors
Berndsen, K., Lis, P., Yeshaw, W. M., Wawro, P. S., Nirujogi, R. S., Wightman, M., Macartney, T., Dorward, M., Knebel, A., Tonelli, F., Pfeffer, S. R., & Alessi, D. R.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2019-10-30
Volume
8
ISSN
2050-084X
DOI
10.7554/elife.50416
PMC
PMC6850886
Cited by
139
References
6
Language
en
Licence
Funders
  • Michael J. Fox Foundation for Parkinson's Research (17298, 6986, Langston Award)
  • Medical Research Council (MC_UU_12016/2)
  • National Institutes of Health (DK37332)

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