Jørgen D. Rønneberg, Martine Hjeltnes, Josephine Krieger, Joshua E. Elias, Maria Stensland, Kristian Holm, Xiaojun Jiang, Chuki Khangsar, Tuula A. Nyman, Arthur Kaser, Johannes R. Hov, Tom H. Karlsen, Nicole C. Kaneider, Frode L. Jahnsen, Georg Schneditz
G protein-coupled receptor 35 (GPR35) has been implicated in cancer, but the functional roles of its isoforms remain unresolved. Here, we characterize GPR35-long, an N-terminally extended epithelial isoform selectively enriched in colorectal cancer and cholangiocarcinoma. Mass spectrometry and immunohistochemistry confirmed GPR35-long protein expression in tumor cells. Functional analyses revealed that GPR35-long supports tumor-associated transcriptional programs, enhances cellular ATP production, and exhibits increased constitutive and ligand-induced beta-arrestin signaling. These phenotypes were selectively suppressed by the inverse agonist CID-2745687, identifying GPR35-long as a functionally distinct isoform with selective pharmacological sensitivity in tumor cells.