PTPRF is a stress responsive cytoskeletal checkpoint that coordinates metabolic adaptation in hepatocytes and β cells

Bansal, M.; St-Pierre-Wijckmans, W.; Negueruela, J.; Buss, C. E.; Ribeiro-Costa, F.; Li, A.; Lai, T.; Nair, V. M.; Vandenbempt, V.; Lisjak, M.; Perez-Chavez, I.; Hovhannisyan, G. G.; Ezerina, D.; Bostanciklioglu, M.; Demine, S.; Yu, L.; Oxley, D.; Mourad, N.; Singh, S. P.; Messens, J.; Balaguer-Roman, A.; Frutos, M.; Martinez, C. M.; Ramos-Molina, B.; Suain, V.; Conrard, L.; Baeyens, N.; Vertommen, D.; Cardozo, A. K.; Gilon, P.; Sharpe, H.; Gilglioni, E. H.; Gurzov, E. N.

doi:10.64898/2026.09.03.748858

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bioRxiv · 10.64898/2026.09.03.748858

PTPRF is a stress responsive cytoskeletal checkpoint that coordinates metabolic adaptation in hepatocytes and β cells

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Abstract

Cytoskeletal remodeling is essential for adaptation to nutrient availability, yet how cells coordinate actin dynamics with glucose homeostasis in metabolic organs remains unclear. Here, we identify a pathway linking metabolic stress to actin reorganization in hepatocytes and pancreatic {beta} cells. This mechanism involves transcriptional repression of the receptor protein tyrosine phosphatase PTPRF by spliced XBP1, a key unfolded protein response factor. In hepatocytes, PTPRF loss under dietary stress enhances insulin signaling, increases mitochondrial respiration and reduces steatosis. Proteomic analyses show that PTPRF interacts with regulators of actin polymerization and cell junctions, and its deletion promotes actin filament organization, shifting metabolism toward oxidative pathways. In {beta} cells, PTPRF deficiency similarly enhances actin polymerization and augments glucose-stimulated insulin secretion in obesity. Collectively, these findings place PTPRF as a nutrient-responsive regulator of cytoskeletal remodeling that coordinates hepatic metabolism and {beta}-cell function, highlighting its potential as a therapeutic target for improving systemic glucose control.

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Bansal, M., St-Pierre-Wijckmans, W., Negueruela, J., Buss, C. E., Ribeiro-Costa, F., Li, A., Lai, T., Nair, V. M., Vandenbempt, V., Lisjak, M., Perez-Chavez, I., Hovhannisyan, G. G., Ezerina, D., Bostanciklioglu, M., Demine, S., Yu, L., Oxley, D., Mourad, N., Singh, S. P., Messens, J., Balaguer-Roman, A., Frutos, M., Martinez, C. M., Ramos-Molina, B., Suain, V., Conrard, L., Baeyens, N., Vertommen, D., Cardozo, A. K., Gilon, P., Sharpe, H., Gilglioni, E. H., Gurzov, E. N.. 2026-09-07. PTPRF is a stress responsive cytoskeletal checkpoint that coordinates metabolic adaptation in hepatocytes and β cells. https://doi.org/10.64898/2026.09.03.748858

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