PXD034966

PXD034966 is an original dataset announced via ProteomeXchange.

Title	Downregulation of RING ligase praja2 boosts receptor tyrosine kinases in kidney cancer
Description	Clear cell renal cell carcinoma (ccRCC) is the most common variant of 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 the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At the molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
HostingRepository	PRIDE
AnnounceDate	2024-05-21
AnnouncementXML	Submission_2024-05-21_12:21:57.232.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	CHIARA D'AMBROSIO
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-29 15:28:45	ID requested
⏵ 1	2024-05-21 12:21:58	announced

Rinaldi L, Chiuso F, Senatore E, Borzacchiello D, Lignitto L, Iannucci R, Donne RD, Fuggi M, Reale C, Russo F, Russo NA, Giurato G, Rizzo F, Sellitto A, Santangelo M, De Biase D, Paciello O, D'Ambrosio C, Amente S, Garbi C, Dalla E, Scaloni A, Weisz A, Ambrosino C, Insabato L, Feliciello A, Downregulation of praja2 restrains endocytosis and boosts tyrosine kinase receptors in kidney cancer. Commun Biol, 7(1):208(2024) [pubmed]

10.1038/s42003-024-05823-4;

submitter keyword: LC-MS-MS,Praja2, interactome

Andrea Scaloni
contact affiliation	Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment (ISPAAM), National Research Council, Piazzale Enrico Fermi 1, 80055 Portici (NA), Italy
contact email	andrea.scaloni@cnr.it
lab head
CHIARA D'AMBROSIO
contact affiliation	ISPAAM CNR
contact email	chiara.dambrosio@cnr.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034966
     1. Label: PRIDE project
     2. Name: Downregulation of RING ligase praja2 boosts receptor tyrosine kinases in kidney cancer