2. Academic Validation
  3. The C-terminal Kinase Domain-Binding and Suppression Motif Prevents Constitutive Activation of FGFR2

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

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.

Figures
Products