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. 2024 Feb 20;7:208. doi: 10.1038/s42003-024-05823-4

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 8 — a Schematic view of the targeted genomic locus of mouse praja2. Following deletion of the Neo Cassette by Flpe and Exon 1 and 2 by Hprt-Cre recombinases, respectively, the constitutive praja2 KO mouse line was obtained. b The offsprings from praja2^+/− intercrosses were genotyped by PCR analysis of tail DNA. Bands corresponding to wild type (466 bp) and KO (320 bp) alleles were obtained using the couples of primers FNFFw/FNFRw and LNLFw/FNFRw, respectively. c Histological examination of kidney samples: hematoxylin/eosin (H/E) (a′, b′) and ERG-immunolabeled nuclei of endothelial cells (c′, d′) are shown. Magnification 40X. Wild-type kidney samples (a′–c′) show unremarkable histopathological changes. In praja2 KO kidneys (b′–d′), a prominent, ectatic dilatation of vessels bound only by a very slender and flattened endothelium was evident. Vascular enlargement and ectasia are bordered by ERG-immunolabeled nuclei (arrows) consisting of endothelium (d′). d Immunohistochemistry analysis for EGFR, VEGFR, and ERG in renal tissues from control (c57, left panels) and praja2 KO mice (79, right panels). Magnification 106×. e Growth factor binding to its cognate receptor (receptor tyrosine kinase, RTK) at cell membrane induces receptor activation and signaling. Ubiquitylation of the adapter protein AP2m1 by praja2 regulates receptor endocytosis and clearance, thus attenuating the mitogenic cascade. Downregulation of praja2 in clear cell carcinoma by oncogenic miRNAs and the proteasome impairs endocytosis and supports RTK signaling and cancer cell growth.