Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3

Tavormina, Patricia L.; Shiang, Rita; Thompson, Leslie M.; Zhu, Yazhen; Wilkin, Douglas J.; Lachman, Ralph S.; Wilcox, William R.; Rimoin, David L.; Cohn, Daniel H.; Wasmuth, John J.

doi:10.1038/ng0395-321

Cited by 575 publications

(397 citation statements)

References 30 publications

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“…The K650E mutation in FGFR3, originally identified as the cause of the neonatal lethal skeletal malformation syndrome Thanatophoric Dysplasia type II (38), has been identified frequently as a somatic mutation in many different human cancers such as bladder cancer and multiple myeloma (1). This mutation has been exploited in many studies to examine signaling pathways utilized by FGFR3 (14,(39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Using titanium dioxide-based phosphopeptide enrichment (TiO 2 )-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it was demonstrated that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase-dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain.Implications: These results demonstrate that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target, but that phosphorylated tyrosine residues within the TACC3-derived portion are not critical for activity.

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Section: Discussionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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“…Activating mutations at di erent positions to c-fms and c-kit have also been found within the A loops of the RET and FGF receptors (Tavormina et al, 1995). Both the RET and c-kitD814V activating loop mutations cause a shift in peptide phosphorylation speci®city of the receptors, which led to the suggestion that this may cause cell transformation through phosphorylation of inappropriate substrates (Songyang et al, 1995;Piao et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

et al. 1999

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Expression of a receptor for human macrophage-colony stimulating factor (M-CSF or CSF-1), containing a point mutation which changes an aspartate to a valine at position 802 of the activating loop of the kinase domain, potently transforms the haemopoietic cell line FDC-P1 yet prevents Rat-2 ®broblast transformation. In order to understand this apparent paradox, aspartate 802 was changed by cassette mutagenesis to each of the other 19 amino acids. All hydrophobic amino acid substitutions were transforming when tested in FDC-P1 cells yet inactivating when tested in Rat-2 ®broblasts. These same amino acid substitutions also activated receptor degradation, strongly suggesting a causal relationship between receptor degradation and inactivation in ®broblasts. Point mutations or small deletions of Y708 within the kinase insert region of the mutant D802V receptor partly inhibited receptor degradation. The more stable D802V receptor derivatives were able to transform both FDC-P1 cells and Rat-2 ®broblasts, so establishing that the cell speci®c e ect of the c-fmsD802V activating loop mutation is attributable to receptor degradation which accompanies kinase activation and prevents the transformation of Rat-2 but not of FDC-P1 cells.

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“…Missense mutations in the transmembrane region of FGFR3 result in constitutive activation and the autosomal dominant heritable disorders of skeletal development such as thanatophoric dwarfism, achondroplasia and Crouzon syndrome (Tavormina et al, 1995;Naski et al, 1996;Bonaventure et al, 2001). The phenotype observed in dwarfism suggests that the dysregulation of FGFR3 could impair cell growth and differentiation (Su et al, 1997;LegeaiMallet et al, 1998;Sahni et al, 1999), knockout mouse studies confirming an inhibitory role for FGFR3 in bone growth (Colvin et al, 1996;Deng et al, 1996).…”

mentioning

confidence: 99%

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

Merrick

2003

Br J Cancer

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Fibroblast growth factor receptor 3 (FGFR3) is one of four high-affinity tyrosine kinase receptors for the FGF family of ligands, frequently associated with growth arrest and induction of differentiation. The extracellular immunoglobulin (IgG)-like domains II and III are responsible for ligand binding; alternative usage of exons IIIb and IIIc of the Ig-like domain III determining the ligand-binding specificity of the receptor. By reverse transcriptase polymerase chain reaction (RT -PCR) a novel FGFR3IIIc variant FGFR3IIIS, expressed in a high proportion of tumours and tumour cell lines but rarely in normal tissues, has been identified. Unlike recently described nonsense transcripts of FGFR3, the coding region of FGFR3IIIS remains in-frame producing a novel protein. The protein product is coexpressed with FGFR3IIIc in the membrane and soluble cell fractions; expression in the soluble fraction is decreased after exposure to bFGF but not aFGF. Knockout of FGFR3IIIS using antisense has a growth-inhibitory effect in vitro, suggesting a dominantnegative function for FGFR3IIIS inhibiting FGFR3-induced growth arrest. In summary, alternative splicing of the FGFR3 Ig-domain III represents a mechanism for the generation of receptor diversity. FGFR3IIIS may regulate FGF and FGFR trafficking and function, possibly contributing to the development of a malignant phenotype.

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Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3

Cited by 575 publications

References 30 publications

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

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