Phosphoproteomic insights into processes influenced by the kinase-like protein DIA1/C3orf58

Hareza, Agnieszka; Bakun, Magda; Świderska, Bianka; Dudkiewicz, Małgorzata; Koscielny, Alicja; Bajur, Anna T.; Jaworski, Jacek; Dadlez, Michał; Pawłowski, Krzysztof

doi:10.7717/peerj.4599

Cited by 7 publications

(10 citation statements)

References 78 publications

(102 reference statements)

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“…We first tested the effect of INK128, an adenosine triphosphate-competitive inhibitor of mTOR that influences the activity of both mTORC1 and mTORC2, on cargo trafficking through the ER and GA. We used the RUSH method [ 29 , 32 ] to visualize the trafficking of model cargo (vesicular stomatitis virus G protein [VSVg]) in living HeLa cells. In this method, the addition of free biotin, which disrupts the interaction between streptavidin-tagged ER anchor (Ii protein), and VSVg that is fused to streptavidin binding peptide and green fluorescent protein (GFP), triggers trafficking of the latter in the secretory pathway, which can be visualized by spinning-disc microscopy [ 29 , 32 ]. We chose to study HeLa cells because the RUSH system was optimized with this cell line, and these cells are often used for studies that focus on mTOR.…”

Section: Resultsmentioning

confidence: 99%

mTOR controls endoplasmic reticulum–Golgi apparatus trafficking of VSVg in specific cell types

et al. 2021

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Background Mammalian/mechanistic target of rapamycin (mTOR) complexes are essential for cell proliferation, growth, differentiation, and survival. mTORC1 hyperactivation occurs in the tuberous sclerosis complex (TSC). mTORC1 localizes to the surface of lysosomes, where Rheb activates it. However, mTOR was also found on the endoplasmic reticulum (ER) and Golgi apparatus (GA). Recent studies showed that the same inputs regulate ER-to-GA cargo transport and mTORC1 (e.g., the level of amino acids or energy status of the cell). Nonetheless, it remains unknown whether mTOR contributes to the regulation of cargo passage through the secretory pathway. Methods The retention using selective hooks (RUSH) approach was used to image movement of model cargo (VSVg) between the ER and GA in various cell lines in which mTOR complexes were inhibited. We also investigated VSVg trafficking in TSC patient fibroblasts. Results We found that mTOR inhibition led to the overall enhancement of VSVg transport through the secretory pathway in PC12 cells and primary human fibroblasts. Also, in TSC1-deficient cells, VSVg transport was enhanced. Conclusions Altogether, these data indicate the involvement of mTOR in the regulation of ER-to-GA cargo transport and suggest that impairments in exocytosis may be an additional cellular process that is disturbed in TSC.

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Section: Resultsmentioning

confidence: 99%

mTOR controls endoplasmic reticulum–Golgi apparatus trafficking of VSVg in specific cell types

et al. 2021

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“…A PSI-BLAST search using VLK as a query produces another small family of potential secreted kinases that includes Fam69A, Fam69B, Fam69C, DIA1, and DIA1R. Very little is known about these proteins ( 21 , 22 , 23 ).…”

Section: Secreted Kinasesmentioning

confidence: 99%

The ABCs of the atypical Fam20 secretory pathway kinases

Worby

Mayfield

Pollak

et al. 2021

Journal of Biological Chemistry

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The study of extracellular phosphorylation was initiated in late 19th century when the secreted milk protein, casein, and egg-yolk protein, phosvitin, were shown to be phosphorylated. However, it took more than a century to identify Fam20C, which phosphorylates both casein and phosvitin under physiological conditions. This kinase, along with its family members Fam20A and Fam20B, defined a new family with altered amino acid sequences highly atypical from the canonical 540 kinases comprising the kinome. Fam20B is a glycan kinase that phosphorylates xylose residues and triggers peptidoglycan biosynthesis, a role conserved from sponges to human. The protein kinase, Fam20C, conserved from nematodes to humans, phosphorylates well over 100 substrates in the secretory pathway with overall functions postulated to encompass endoplasmic reticulum homeostasis, nutrition, cardiac function, coagulation, and biomineralization. The preferred phosphorylation motif of Fam20C is SxE/pS, and structural studies revealed that related member Fam20A allosterically activates Fam20C by forming a heterodimeric/tetrameric complex. Fam20A, a pseudokinase, is observed only in vertebrates. Loss-of-function genetic alterations in the Fam20 family lead to human diseases such as amelogenesis imperfecta, nephrocalcinosis, lethal and nonlethal forms of Raine syndrome with major skeletal defects, and altered phosphate homeostasis. Together, these three members of the Fam20 family modulate a diverse network of secretory pathway components playing crucial roles in health and disease. The overarching theme of this review is to highlight the progress that has been made in the emerging field of extracellular phosphorylation and the key roles secretory pathway kinases play in an ever-expanding number of cellular processes.

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“…Very little is known about these proteins outside of their potential link to neurological diseases. Analysis of cells overexpressing DIA1 shows an increase in phosphosites with a preference for [ST]P and Sx[DE]/Sxx[DE]/S[DE] motifs .…”

Section: Secreted Human Kinasesmentioning

confidence: 99%

Thinking outside of the cell: Secreted protein kinases in bacteria, parasites, and mammals

2019

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Previous decades have seen an explosion in our understanding of protein kinase function in human health and disease. Hundreds of unique kinase structures have been solved, allowing us to create generalized rules for catalysis, assign roles of communities within the catalytic core, and develop specific drugs for targeting various pathways. Although our understanding of intracellular kinases has developed at a fast rate, our exploration into extracellular kinases has just begun. In this review, we will cover the secreted protein kinase families found in humans, bacteria, and parasites. © 2019 IUBMB Life, 71(6):749–759, 2019

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Phosphoproteomic insights into processes influenced by the kinase-like protein DIA1/C3orf58

Cited by 7 publications

References 78 publications

mTOR controls endoplasmic reticulum–Golgi apparatus trafficking of VSVg in specific cell types

mTOR controls endoplasmic reticulum–Golgi apparatus trafficking of VSVg in specific cell types

The ABCs of the atypical Fam20 secretory pathway kinases

Thinking outside of the cell: Secreted protein kinases in bacteria, parasites, and mammals

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