Dataset Information

AD and FTLD model mouse, brain, Phosphoproteome

ABSTRACT: Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in five types of Alzheimer's disease (AD) mouse models (5xFAD, APP-tg, PS1-tg, PS2-tg and APP-KI) and four types of frontotemporal lobar degeneration (FTLD) mouse models(CHMP2B-KI, PGRN-KI, VCP-KI and TDP43-KI) at multiple time points (1, 3 and 6 months).

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Frontotemporal Dementia,Alzheimer's Disease

SUBMITTER: Hidenori Homma

LAB HEAD: Hitoshi Okazawa

PROVIDER: PXD027119 | Pride | 2021-09-07

REPOSITORIES: Pride

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Publications

Prediction and verification of the AD-FTLD common pathomechanism based on dynamic molecular network analysis.

Jin Meihua M Jin Xiaocen X Homma Hidenori H Fujita Kyota K Tanaka Hikari H Murayama Shigeo S Akatsu Hiroyasu H Tagawa Kazuhiko K Okazawa Hitoshi H

Communications biology 20210812 1

Multiple gene mutations cause familial frontotemporal lobar degeneration (FTLD) while no single gene mutations exists in sporadic FTLD. Various proteins aggregate in variable regions of the brain, leading to multiple pathological and clinical prototypes. The heterogeneity of FTLD could be one of the reasons preventing development of disease-modifying therapy. We newly develop a mathematical method to analyze chronological changes of PPI networks with sequential big data from comprehensive phosph ...[more]

PMID: 34385591

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Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Method: Expression studies of RING ligase praja2 and tyrosine kinase receptors (RTKs) in renal cell carcinoma was evaluated by immunoblot and immunohistochemistry. Gene transcription profiling in RCC cells was evaluated by RNA sequencing and Ingenuity Pathway Analysis. Imunofluorescence assays were used to evaluate the intracellular distribution and clearance of membrane receptors in cells devoid of praja2. Ubiquitin modifications and protein-protein interaction networks were monitored by IP, western blot, mass spectrometry and proteomic analysis. Experiments in vitro and in vivo were performed to define the role of praja2 in RTKs turnover, metabolism, renal cell carcinoma growth and metastatic diffusion. Results: We report here that the ubiquitin ligase praja2 controls endocytosis and the signal strength of different types of receptors (EGFR, VEGFR, TfR). Praja2 forms a complex with- and ubiquitinates the adaptor protein AP2m required for the activity of ATPase and acidification of endosomes and lysosomes necessary for receptor endocytosis and clearance. Downregulation of praja2 blocks the endocytosis of several membrane receptors, including EGFR, VEGFR and TfR and amplifies mitogenic and proliferative signaling as shown in the clear cell renal cell carcinoma (ccRCC). Restoring praja2 expression in RCC cells reduces EGFR levels, rewires cancer cell metabolism and inhibits growth and metastatic diffusion. In vivo, praja2 knockout mice show upregulation of tyrosine kinase receptors (RTKs) and pronounced histopathological renal alterations. Conclusion: Our findings identify praja2 as an important regulator of tyrosine kinase receptor(s) turnover and can be considered a bona fide oncosuppressor because it finely regulates signaling of several types of receptors and its loss supports kidney cancer growth and diffusion.

Dataset Information

AD and FTLD model mouse, brain, Phosphoproteome

Publications

Prediction and verification of the AD-FTLD common pathomechanism based on dynamic molecular network analysis.

Similar Datasets

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