Cell Biology of Membrane Trafficking in Human Disease

Howell, Gareth; Holloway, Zoe G.; Cobbold, Christian; Monaco, Anthony P.; Ponnambalam, Sreenivasan

doi:10.1016/s0074-7696(06)52005-4

Cited by 60 publications

(48 citation statements)

References 401 publications

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“…However, detection of the protein in the plasma membrane by Western blot analysis and confocal microscopy means that normal transport of the mutant protein from the ER to the Golgi, and finally to the plasma membrane does occur safely. Therefore, FOP is different from several other genetic disorders, which show defective protein folding or ER retention (62)(63). Our data provide clear evidence that the mutant R206H is in a functionally active state without defective folding despite its low levels of expression and minor activity.…”

Section: Discussionmentioning

confidence: 64%

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Song

Kim²,

Woo

et al. 2010

Journal of Biological Chemistry

103

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Fibrodysplasia ossificans progressiva (FOP), a rare genetic and catastrophic disorder characterized by progressive heterotopic ossification, is caused by a point mutation, c.617G>A; p.R206H, in the activin A receptor type 1 (ACVR1) gene, one of the bone morphogenetic protein type I receptors (BMPR-Is). Although altered BMP signaling has been suggested to explain the pathogenesis, the molecular consequences of this mutation are still elusive. Here we studied the impact of ACVR1 R206H mutation on BMP signaling and its downstream signaling cascades in murine myogenic C2C12 cells and HEK 293 cells. We found that ACVR1 was the most abundant of the BMPR-Is expressed in mesenchymal cells but its contribution to osteogenic BMP signal transduction was minor. The R206H mutant caused weak activation of the BMP signaling pathway, unlike the Q207D mutant, a strong and constitutively active form. The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-␤ or BMP signaling. The decreased binding affinity of FKBP1A to the mutant R206H ACVR1 resulted in leaky activation of the BMP signal, and moreover, it decreased steady-state R206H ACVR1 protein levels. Interestingly, while WT ACVR1 and FKBP1A were broadly distributed in plasma membrane and cytoplasm without BMP-2 stimulation and then localized in plasma membrane on BMP-2 stimulation, R206H ACVR1 and FKBP1A were mainly distributed in plasma membrane regardless of BMP-2 stimulation. The impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may result in mild activation of osteogenic BMP-signaling in extraskeletal sites such as muscle, which eventually lead to delayed and progressive ectopic bone formation in FOP patients.

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Section: Discussionmentioning

confidence: 64%

Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva

Song

Kim²,

Woo

et al. 2010

Journal of Biological Chemistry

103

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“…Copper transport is highly regulated in the cell and involves transport into the endoplasmic reticulum, as well as through secretory and vacuolar pathways for delivery to copper-dependent enzymes, copper excretion and copper detoxification (Yuan et al, 1997;Howell et al, 2006;Gonzalez et al, 2008;Jo et al, 2008;Jo et al, 2009). GO biological process category enrichment for cell growth in low-copper conditions revealed the importance of the AP1 adaptor complex, the AP3 adaptor complex, the HOPS complex, the clathrin adaptor complex and the Golgi-to-vacuole transport pathway.…”

Section: Disease Models and Mechanisms Dmmmentioning

confidence: 99%

Combined zebrafish-yeast chemical-genetic screens reveal gene–copper-nutrition interactions that modulate melanocyte pigmentation

Ishizaki

Spitzer

Wildenhain

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu2+) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks.

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“…Membrane and protein components traffic from the endoplasmic reticulum and Golgi apparatus to their destinations in the different organelles and the plasma membrane. [17][18][19] Since Vmp1 is an ER-resident protein, …”

Section: Vmp1 Disruption In Dictyostelium Autophagy and Much Morementioning

confidence: 99%