The retromer complex in development and disease

Wang, Shiuan; Bellen, Hugo J.

doi:10.1242/dev.123737

Cited by 79 publications

(60 citation statements)

References 55 publications

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“…Thus, perturbation of retromer is linked to pathologies like metabolic myopathy, neurodegenerative disorders, etc. (Wang and Bellen, 2015;Small and Petsko, 2015). Retromer also interacts with WASH (Wiskott-Aldrich syndrome protein and Scar homologue), an endosomal actin nucleator, to facilitate cargo sorting (Harbour et al, 2010;Derivery et al, 2009;McGough et al, 2014).…”

Section: Mt1-mmp-mediated Ecm Degradationmentioning

confidence: 99%

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Sharma

Parveen

Shah

et al. 2019

Journal of Cell Biology

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A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECM degradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, we demonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity by recycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressed metalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were located on the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrix degradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromer could directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed or frequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell lines showed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumor samples.

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Section: Mt1-mmp-mediated Ecm Degradationmentioning

confidence: 99%

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Sharma

Parveen

Shah

et al. 2019

Journal of Cell Biology

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“…The complex is essential for maintenance of neurons and has been implicated in the etiology of a number of neurodegenerative disorders 25 .…”

Section: Smr Analysismentioning

confidence: 99%

Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders

Byrne

Zhu

et al. 2019

Preprint

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Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium -schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genomewide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes.However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. In addition, we identified a number of variants that approached genome-wide significance in the original GWAS and have larger conditional effect sizes after conditioning on the other disorders. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.

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“…Retromer is an evolutionarily conserved protein complex that orchestrates sorting and export of integral membrane proteins from the endosome. Loss of Retromer function, which is implicated in a variety of disease conditions, results in increased rates of turnover of plasma membrane proteins and retrograde cargo proteins in the lysosome, with broad consequences to cell and organism physiology (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Retromer forms low order oligomers on supported lipid bilayers

Deatherage

Nikolaus

Karatekin

et al. 2020

Preprint

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Retromer is a protein sorting device that orchestrates the selection and export of integral membrane proteins from the endosome via retrograde and plasma membrane recycling pathways. Long standing hypotheses regarding the Retromer sorting mechanism posit that oligomeric interactions between Retromer and associated accessory factors on the endosome membrane drives clustering of Retromer-bound integral membrane cargo prior to its packaging into a nascent transport carrier. To test this hypothesis, we examined interactions between the components of the SNX3-Retromer sorting pathway using quantitative single particle fluorescence microscopy of a reconstituted system comprising a supported bilayer, Retromer, a model cargo protein, the accessory proteins SNX3, RAB7, and the Retromer-binding segment of the WASHC2C subunit of the WASH complex. The predominant species of membrane associated Retromer are low order: monomers (~18%), dimers (~35%), trimers (~24%) and tetramers (~24%). Unexpectedly, neither cargo nor accessory factors promote Retromer oligomerization on a supported bilayer. The results indicate that Retromer has an intrinsic propensity to form low order oligomers and that neither membrane association nor accessory factors potentiate oligomerization. Hence, Retromer is a minimally concentrative sorting device adapted to bulk membrane trafficking from the endosomal system.

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The retromer complex in development and disease

Cited by 79 publications

References 55 publications

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders

Retromer forms low order oligomers on supported lipid bilayers

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