The C-terminal Kinase Domain-Binding and Suppression Motif Prevents Constitutive Activation of FGFR2

  • Cancer Res. 2025 Jun 24. doi: 10.1158/0008-5472.CAN-24-3349.
Daniel Zingg  1 ,  Chi-Chuan Lin  2 ,  Julia Yemelyanenko  3 ,  Lukasz Wieteska  4 ,  Sjors M Kas  3 ,  Onno B Bleijerveld  5 ,  Xue Chao  6 ,  Jinhyuk Bhin  7 ,  Catrin Lutz  3 ,  Ellen Wientjens  3 ,  Sjoerd Klarenbeek  8 ,  Giulia Zanetti  3 ,  Stefano Annunziato  3 ,  Bjørn Siteur  9 ,  Eline van der Burg  3 ,  Anne Paulien Drenth  3 ,  Marieke van de Ven  3 ,  Lodewyk F A Wessels  10 ,  Maarten Altelaar  11 ,  John E Ladbury  2 ,  Jos Jonkers  3
Affiliations
  • 1. Genentech, United States.
  • 2. University of Leeds, Leeds, United Kingdom.
  • 3. The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 4. University of Pittsburgh, United States.
  • 5. The Netherlands Cancer Institute, Amsterdam, Noord-Holland, Netherlands.
  • 6. Sun Yat-sen University Cancer Center, Guangzhou, State..., China.
  • 7. Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Seoul, Korea (South), Republic of.
  • 8. Royal GD (Netherlands), Deventer, Netherlands.
  • 9. The Netherlands Cancer Institute (NKI), Amsterdam, Netherlands.
  • 10. The Netherlands Cancer Institute, Amsterdam, NH, Netherlands.
  • 11. Utrecht University, Utrecht, Netherlands.
PMID: 40554806 DOI: 10.1158/0008-5472.CAN-24-3349
Abstract

Genetic alterations in receptor tyrosine kinase (RTK) genes can generate potent oncogenic drivers. Truncation of the Fibroblast Growth Factor receptor 2 (FGFR2) gene by its last exon 18 (E18) is caused by structural alterations, such as focal amplifications and gene fusions/rearrangements, as well as by mutations. All the E18-truncating FGFR2 variants (FGFR2ΔE18) act as strong driver alterations in Cancer, and they commonly encode a receptor lacking the carboxy (C)-terminal tail. Here, we analyzed a compendium of Fgfr2-E18 variants to uncover the mechanism by which loss of the C-tail renders FGFR2 oncogenic. While permutation of previously annotated C-terminal FGFR motifs did not recapitulate the tumorigenicity of FGFR2ΔE18, the functional annotation efforts led to the discovery of a C-terminal phenylalanine-serine motif that mediates binding of the C-tail to the kinase domain and thereby suppresses FGFR2 kinase activity. Permutation of this kinase domain-binding and suppression (KDBS) motif in conjunction with other FGFR2-regulatory C-terminal sites fully phenocopied the oncogenic competence of FGFR2ΔE18. Together, these findings delineate how the C-terminal tail prevents FGFR2 from aberrant oncogenic activation.

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