The urothelium covers the luminal surface of almost the entire urinary tract, extending from the renal pelvis, through the ureter and bladder, to the proximal urethra. The majority of urothelial carcinomas are bladder carcinomas, and urothelial carcinomas of the renal pelvis and ureter account for only approximately 7% of the total. Urothelial tumors arise and evolve through divergent phenotypic pathways. Some tumors progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumors. More aggressive variants arise either from flat, high-grade carcinoma in situ (CIS) and progress to invasive tumors, or they arise de novo as invasive tumors. Low-grade papillary tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. In contrast, CIS and invasive tumors frequently show alterations in the TP53 and RB genes and pathways. Invasion and metastases are promoted by several factors that alter the tumor microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF). Phosphorylation sites were added based on information from PhosphoSitePlus (R), https://www.phosphosite.org. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2828 CPTAC Assay Portal] c0b b1b d0d d79 fca parentid=P06400; parentsymbol=RB1; site=strPPtLsPIPHIPr; position=ser780; sitegrpid=447978; ptm=p; direction=d parentid=O75582; parentsymbol=RPS6KA5; site=PDNQPLKtPCFTLHY; position=thr581; sitegrpid=448217; ptm=p; direction=u parentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=u parentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGTRSY; position=ser222; sitegrpid=448513; ptm=p; direction=u parentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGTRSY; position=ser226; sitegrpid=448074; ptm=p; direction=u parentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=u parentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyR; position=tyr187; sitegrpid=447594; ptm=p; direction=u parentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=u a4f a4f a4f fd5 a4f a4f a4f a4f a4f a4f a4f a4f a4f a4f a4f a4f a4f 25514926 PubMed PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 2015 Hornbeck PV Zhang B Murray B Kornhauser JM Latham V Skrzypek E bladder disease DOID:365 Disease urinary bladder cancer DOID:11054 Disease bladder urothelial cell CL:1001428 Cell Type cancer pathway PW:0000605 Pathway Ontology cancer DOID:162 Disease 22417847 PubMed Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer. Hum Pathol 2012 Juanpere N Agell L Lorenzo M de Muga S Lأ³pez-Vilarأ³ L Murillo R Mojal S Serrano S Lorente JA Lloreta J Hernأ،ndez S 23175443 PubMed Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 2013 Williams SV Hurst CD Knowles MA map05219 KEGG Pathway Bladder Cancer Pathway http://www.genome.jp/dbget-bin/www_bget?pathway:map05219 disease pathway PW:0000013 Pathway Ontology 24122582 PubMed PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer 2014 Calderaro J Rebouissou S de Koning L Masmoudi A Hأ©rault A Dubois T Maille P Soyeux P Sibony M de la Taille A Vordos D Lebret T Radvanyi F Allory Y papillary renal cell carcinoma DOID:4465 Disease 22899908 PubMed A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges. Adv Urol 2012 di Martino E Tomlinson DC Knowles MA 16474624 PubMed Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. http://www.ncbi.nlm.nih.gov/pubmed/16474624 2005 Wolf EM Liang G Jones PA