PIN4 is a FGFR3-TACC3 substrate required for ROS-mediated induction of PGCIα and tumor growth.

  • Major finding: PIN4 is a FGFR3–TACC3 substrate required for ROS-mediated induction of PGCIα and tumor growth.

  • Concept: FGFR3–TACC3 induces peroxisome biogenesis and protein synthesis through PIN4 phosphorylation.

  • Impact: Inhibitors of oxidative phosphorylation may have therapeutic potential in FGFR3–TACC3+ tumors.

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A chromosomal translocation generating the in-frame oncogenic gene fusion FGFR3–TACC3 occurs in 3% of human glioblastomas, and was subsequently observed in a number of other tumor types. FGFR3–TACC3 renders cells sensitive to FGFR inhibition, but the FGFR3–TACC3 downstream effectors have not been elucidated. Frattini and colleagues sought to identify the transcriptional changes induced by FGFR3–TACC3. Gene expression profiling of human astrocytes expressing FGFR3–TACC3 or kinase dead FGFR3–TACC3 K508M, and FGFR3–TACC3-expressing astrocytes treated with an FGFR inhibitor revealed that FGFR3–TACC3 activates mitochondrial biogenesis and metabolism genes. Consistent with these findings, mitochondrial inhibitors reduced FGFR3–TACC3-expressing cell viability and suppressed the growth of FGFR3–TACC3+ glioma xenografts. Anti-phosphotyrosine immunoprecipitation followed by LC/MS-MS identified PIN4, which is phosphorylated in the activation of mitochondrial metabolism, as an FGFR3–TACC3 substrate, and tumors expressing FGFR3–TACC3 exhibited high levels of phospho-PIN4. FGFR3–TACC3 phosphorylated PIN4 on Y122, and mutations preventing PIN4 phosphorylation disrupted mitochondrial metabolism and ATP production. Mechanistically, PIN4 phosphorylation was required for FGFR3–TACC3-mediated increase in peroxisome biogenesis and protein synthesis. These processes produced intracellular reactive oxygen species (ROS) that upregulated PGCIα, a master regulator of mitochondrial biogenesis and metabolism, to enable tumor growth. Accordingly, PGCIα depletion reduced FGFR3–TACC3 tumor cell growth in vitro and in vivo. In addition to identifying PIN4 as an FGFR3–TACC3 substrate, these findings indicate that FGFR3–TACC3+ tumors depend on mitochondrial respiration, suggesting the potential for therapeutic targeting of oxidative phosphorylation in these tumors.

Frattini V, Pagnotta SM, Tala, Fan JJ, Russo MV, Lee SB, et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 2018;553:222–7.

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