MKK6 binds and regulates expression of Parkinson’s disease‐related protein LRRK2

Hsu, Cindy H.; Chan, D.; Greggio, Elisa; Saha, Sudipta; Guillily, Maria D.; Ferree, Andrew; Raghavan, Kesav; Shen, Grace C.; Segal, Lilach; Ryu, Hoon; Cookson, Mark; Wolozin, Benjamin

doi:10.1111/j.1471-4159.2010.06568.x

Cited by 93 publications

(89 citation statements)

References 44 publications

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“…18,19 Previous in-vitro kinase assays reported that recombinant wild-type or (G2019S) LRRK2 phosphorylated MKK3, MKK4, MKK6, or MKK7 and that (G2019S) mutation augmented LRRK2-mediated phosphorylating of MKK6 or MKK7. 35,36 In the present study, our quantitative phosphoproteomic analysis identified MKK4 phosphorylated at Ser 257 residue as one of the upregulated phosphoproteins in the SN of (G2019S) LRRK2 mice, which are likely to be substrates of (G2019S) LRRK2-mediated phosphorylation in vivo (Chen et al, unpublished results). Thus, we hypothesized that (G2019S) LRRK2 mutation exerts a gain-of-function and enhancing effect on LRRK2 kinase activity, leading to overphosphorylation of MKK4 Ser257 , abnormal activation of MKK4-mediated cell death pathway and degeneration of SNpc Figure 7 Active caspase-9, caspase-8 and caspase-3 were expressed in the SN of (G2019S) LRRK2 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

154

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(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

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Section: Discussionmentioning

confidence: 99%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

154

151

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“…At the top layer is a kinase identified as MAP3K that is able to phosphorylate and activate a MAP2K in the second layer, which consequently activates the final MAPK, thus inducing a change in transcription. LRRK2 was able to bind to and phosphorylate MAP2K, ‐3, ‐4, ‐6 and potentially ‐7 in vitro 70, 71. Furthermore, a G2019S ‐LRRK2 transgenic mouse model showed degeneration of dopaminergic neurons in the substantia nigra concomitant with hyperphosphorylation of MAP2K4 72.…”

Section: Signalling Pathways Through Lrrk2mentioning

confidence: 96%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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“…1). LRRK2 physically interacts with many proteins, such as microtubules [40][41][42][43], 14-3-3 proteins [44,45], mitogen-activated protein kinase 6 [46], and Wnt signaling pathway proteins [47]. Therefore, LRRK2 may also function as a scaffold for many signaling pathways and might therefore be implicated in the number of cellular functions [48].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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MKK6 binds and regulates expression of Parkinson’s disease‐related protein LRRK2

Cited by 93 publications

References 44 publications

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Cellular processes associated with LRRK2 function and dysfunction

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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