Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila

Imai, Yuzuru; Gehrke, Stephan; Wang, Hua Qin; Takahashi, Ryōsuke; Hasegawa, Kazuko; Oota, Etsuro; Lu, Bingwei

doi:10.1038/emboj.2008.163

Cited by 395 publications

(572 citation statements)

References 40 publications

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“…This pattern of binding is consistent with the patterns observed for other LRRK2 binding proteins, including mitogen activated kinase kinases (MKKs) and c-Jun N-terminal Kinase-interacting proteins (JIP) (10,11); the binding sites for other putative binding proteins such as Fas-associated protein with death domain (FADD), moesin, Rab5, 14-3-3, ArhGef7, and 4E-BP are not known (16,(35)(36)(37)(38)(39) (40,41). LRRK2 also binds to itself and to LRRK1 as homo-and heterodimers (22,23,31,42).…”

Section: Discussionmentioning

confidence: 55%

“…LRRK2 kinase activity also does not meet these strict criteria because only the G2019S LRRK2 mutation has been consistently shown to increase kinase activity (36,42,43). Binding of LRRK2 to proteins such as 4E-BP either is not affected by disease-linked mutations or has not been investigated (37). FADD is the only LRRK2 binding protein that show consistent changes in binding (increased) with a panel of multiple disease-linked LRRK2 mutations (35).…”

Section: Discussionmentioning

confidence: 99%

“…The ability of LRRK2 to bind reversibly to membranes might allow it to act as a scaffold able to translocate to the membrane to promote formation of Rac1/PAK/actin complexes. These Rac1/PAK/actin complexes regulate membrane-associated functions such as neurite outgrowth, endocytosis (suggested by the interaction of LRRK2 with Rab5) and apoptosis (suggested by the interaction of LRRK2 with FADD) (16,(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

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Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Chan¹,

Citro²,

Cordy³

et al. 2011

Journal of Biological Chemistry

109

111

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are currently the most common genetic cause of familial late-onset Parkinson disease, which is clinically indistinguishable from idiopathic disease. The most common pathological mutation in LRRK2, G2019S LRRK2, is known to cause neurite retraction. However, molecular mechanisms underlying regulation of neurite length by LRRK2 are unknown. Here, we demonstrate a novel interaction between LRRK2 and the Rho GTPase, Rac1, which plays a critical role in actin cytoskeleton remodeling necessary for the maintenance of neurite morphology. LRRK2 binds strongly to endogenous or expressed Rac1, while showing weak binding to Cdc42 and no binding to RhoA. Co-expression with LRRK2 increases Rac1 activity, as shown by increased binding to the p21-activated kinase, which modulates actin cytoskeletal dynamics. LRRK2 constructs carrying mutations that inactivate the kinase or GTPase activities do not activate Rac1. Interestingly, LRRK2 does not increase levels of membrane-bound Rac1 but dramatically changes the cellular localization of Rac1, causing polarization, which is augmented further when LRRK2 is co-expressed with constitutively active Rac1. Four different disease-related mutations in LRRK2 altered binding to Rac1, with the G2019S and R1441C LRRK2 mutations attenuating Rac1 binding and the Y1699C and I2020T LRRK2 mutations increasing binding. Co-expressing Rac1 in SH-SY5Y cells rescues the G2019S mutant phenotype of neurite retraction. We hypothesize that pathological mutations in LRRK2 attenuates activation of Rac1, causing disassembly of actin filaments, leading to neurite retraction. The interactions between LRRK2 and Rho GTPases provide a novel pathway through which LRRK2 might modulate cellular dynamics and contribute to the pathophysiology of Parkinson disease. Parkinson disease (PD)2 is the most common neurodegenerative movement disorder affecting nearly 1% of elderly over 65 years old. Idiopathic PD may result from a combination of factors including age, genetic predisposition, environmental toxins, and neuroinflammation (1, 2). Mutations in LRRK2 are the most common genetic cause of PD and also contribute to many sporadic cases of PD (3, 4). At least 20 mutations identified to date in LRRK2 cause autosomal-dominant PD, accounting for ϳ7% of all familial cases (4, 5). The missense mutation, G2019S, in the kinase domain of LRRK2 is by far the most common of the LRRK2 mutations associated with PD, and disease associated with the G2019S mutations is clinically indistinguishable from idiopathic disease (6).The Lrrk2 gene of 51 exons encodes a large, multidomain protein that includes an ankyrin repeat and leucine-rich repeat regions (6). The kinase domain of LRRK2 shares homology with receptor-interacting protein kinases and mixed lineage kinases (3, 7). LRRK2 also contains a Ras-of-complex (ROC) domain that exhibits GTPase activity (8,9). In between these two domains lies a C-terminal of Ras complex (COR) domain. Each of these domains is thought to be important for bindi...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Chan¹,

Citro²,

Cordy³

et al. 2011

Journal of Biological Chemistry

109

111

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“…Resistance of various cancers to mTOR inhibitor treatment indicates that other pathways are implicated in 4E-BP1 inactivation (14). Several serine/threonine kinases have been shown to phosphorylate 4E-BP1, such as p38 MAPK, ERK, PIM2, ATM, CDK1, PLK1, LRRK2, GSK3β, and CK1e (15)(16)(17)(18)(19)(20)(21)(22)(23). We recently demonstrated that cyclin-dependent kinase 1 (CDK1) phosphorylates 4E-BP1 at canonical sites T37, T46, S65, and T70 during mitosis and generates a high-molecularweight phospho-isoform called δ-4E-BP1, even in the absence of mTOR activity (24).…”

Section: Merkel Cell Polyomavirusmentioning

confidence: 99%

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Velásquez

Cheng

Shuda

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

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“…LRRK2-mediated miRNA regulation is exacerbated by these mutations, whereas a kinase-dead LRRK2 mutant does not affect gene repression [43]. The LRRK2 substrate 4E-BP associates with Argonaute 2, a component of the RNA-induced silencing complex (RISC), and this interaction is promoted by I1915T and G2019S mutants of LRRK2, presumably due to increased phosphorylation of 4E-BP1 [45]. Thus, compared to wild type, the phosphomimetic 4E-BP(TE) is more toxic to dopamine neurons and is more effective than wild-type 4E-BP in attenuating let-7 activity in vivo.…”

Section: Epigenetic Modulation In Familial Parkinson's Diseasementioning

confidence: 99%

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

2013

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Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila

Cited by 395 publications

References 40 publications

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

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