A visual review of the interactome of LRRK2: Using deep‐curated molecular interaction data to represent biology

Porras, Pablo; Duesbury, Margaret; Fabregat, Antonio; Ueffing, Marius; Orchard, Sandra; Gloeckner, Christian Johannes; Hermjakob, Henning

doi:10.1002/pmic.201400390

Cited by 38 publications

(27 citation statements)

References 90 publications

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“…4). These constitute an intricate network of LRRK2 putative functions making it central to two recent bioinformatics articles that have analysed LRRK2 interactome by means of protein-protein interaction databases and repositories of cellular pathways [177,178]. Instead of a clarifying mechanism of LRRK2-PD, this wide range of implicated functions makes interpreting LRRK2 0 s role in disease even more challenging.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…There are many proteins that have been claimed to interact with LRRK2 at least in some conditions. I do not have space to enumerate all of them here, but the interested reader is directed to some recent summary articles that have attempted to report systematically on the strength of evidence for each interaction [75, 76]. Instead, I will focus on a smaller number of examples that illustrate the larger point about localization being related to function, some coming from my own laboratory.…”

Section: Relationship Of the Function Of Lrrk2 To Other Pd Genesmentioning

confidence: 99%

LRRK2 Pathways Leading to Neurodegeneration

Cookson

2015

Curr Neurol Neurosci Rep

119

106

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Mutations in LRRK2 are associated with inherited Parkinson’s disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the path-ophysiology of PD.

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“…Thus, the human ROCO proteins are an attractive protein family to utilize as a model for PPI network analysis, to explore the link between PPI profiles and functional fates. This approach has been previously used for LRRK2 in isolation, [4,5] the DAPK1 interactome has been reviewed, [6] and the comparison between LRRK1 and LRRK2 has been attempted. [7] However, the collective PPI network analysis of the entire human ROCO protein family is a novel contribution.…”

Section: Introductionmentioning

confidence: 99%

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Tomkins

Dihanich²,

Beilina

et al. 2018

Proteomics

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Signal transduction cascades governed by kinases and GTPases are a critical component of the command and control of cellular processes, with the precise outcome partly determined by direct protein–protein interactions (PPIs). Here, we use the human ROCO proteins as a model for investigating PPI signaling events—taking advantage of the unique dual kinase/GTPase activities and scaffolding properties of these multidomain proteins. PPI networks are reported that encompass the human ROCO proteins, developed using two complementary approaches. First, using the recently developed weighted PPI network analysis (WPPINA) pipeline, a confidence-weighted overview of validated ROCO protein interactors is obtained from peer-reviewed literature. Second, novel ROCO PPIs are assessed experimentally via protein microarray screens. The networks derived from these orthologous approaches are compared to identify common elements within the ROCO protein interactome; functional enrichment analysis of this common core of the network identified stress response and cell projection organization as shared functions within this protein family. Despite the presence of these commonalities, the results suggest that many unique interactors and therefore some specialized cellular roles have evolved for different members of the ROCO proteins. Overall, this multi-approach strategy to increase the resolution of protein interaction networks represents a prototype for the utility of PPI data integration in understanding signaling biology.

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A visual review of the interactome of LRRK2: Using deep‐curated molecular interaction data to represent biology

Cited by 38 publications

References 90 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

LRRK2 Pathways Leading to Neurodegeneration

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

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