An epithelial GPR35 isoform supports tumor-associated transcriptional and metabolic phenotypes

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

doi:10.1002/1873-3468.70423

An epithelial GPR35 isoform supports tumor-associated transcriptional and metabolic phenotypes

FEBS Lett. 2026 Aug 1. doi: 10.1002/1873-3468.70423. Online ahead of print.

Authors

Jørgen D Rønneberg^{1

2

3}, Martine Hjeltnes^{1

2}, Josephine Krieger^{1

2}, Joshua E Elias^{4

5}, Maria Stensland^{6

7}, Kristian Holm^{1

2

3}, Xiaojun Jiang^{1

2}, Chuki Khangsar^{1

2}, Tuula A Nyman^{6

7}, Arthur Kaser^{4

5}, Johannes R Hov^{1

2

3

8}, Tom H Karlsen^{1

2

3

8}, Nicole C Kaneider^{4

5}, Frode L Jahnsen⁹, Georg Schneditz^{1

2}

Affiliations

¹ Division of Surgery and Specialized Medicine, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Norway.
² Division of Surgery and Specialized Medicine, Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway.
³ Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Norway.
⁴ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, UK.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.
⁶ Department of Immunology, University of Oslo and Oslo University Hospital, Norway.
⁷ Proteomics Core Facility, University of Oslo and Oslo University Hospital, Norway.
⁸ Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Norway.
⁹ Department of Pathology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway.

PMID: 42541411
DOI: 10.1002/1873-3468.70423

Abstract

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.

Keywords: G protein‐coupled receptor; cell metabolism; cell signaling; colon cancer; molecular pharmacology.

Abstract

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