Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis.

Abstract	We previously reported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.
Authors	Martin Steger, Federico Diez, Herschel S Dhekne, Pawel Lis, Raja S Nirujogi, Ozge Karayel, Francesca Tonelli, Terina N Martinez, Esben Lorentzen, Suzanne R Pfeffer, Dario R Alessi, Matthias Mann
Journal	eLife (Elife) Vol. 6 (11 10 2017) ISSN: 2050-084X [Electronic] England
PMID	29125462 (Publication Type: Journal Article)
Chemical References	Adaptor Proteins, Signal Transducing Carrier Proteins LRP1 protein, human LRP2BP protein, human Low Density Lipoprotein Receptor-Related Protein-1 Low Density Lipoprotein Receptor-Related Protein-2 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 rab GTP-Binding Proteins
Topics	Adaptor Proteins, Signal Transducing Animals Carrier Proteins (metabolism) Cells, Cultured Cilia (metabolism) Fibroblasts (physiology) Gene Knock-In Techniques Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (metabolism) Low Density Lipoprotein Receptor-Related Protein-1 (metabolism) Low Density Lipoprotein Receptor-Related Protein-2 Mass Spectrometry Mice Organelle Biogenesis Phosphorylation Protein Binding Protein Interaction Mapping Proteomics rab GTP-Binding Proteins (metabolism)

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