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Fibroblast Growth Factor 3 (FGF3) int-2

Fibroblast Growth Factor 3 (FGF3) int-2. Brandon Williams. 3/25/03. OBJECTIVES. Biochemical Information Normal Function in Mouse Ear Development Breast Cancer and FGF3. EASY FACTS. 22 FGFs in vertebrates FGF3: Chromosome 11 (humans) Fgf3: Chromosome 7 (mice)

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Fibroblast Growth Factor 3 (FGF3) int-2

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  1. Fibroblast Growth Factor 3 (FGF3)int-2 Brandon Williams 3/25/03

  2. OBJECTIVES • Biochemical Information • Normal Function in Mouse Ear Development • Breast Cancer and FGF3

  3. EASY FACTS • 22 FGFs in vertebrates • FGF3: Chromosome 11 (humans) • Fgf3: Chromosome 7 (mice) • Are secreted polypeptides • Use tyrosine kinase receptors for signaling • Proto-oncogene

  4. FUNCTIONS • Cell proliferation, migration, and differentiation during embryonic development • Tissue repair, injury response in adults • Angiogenesis

  5. FGF and Tyrosine Kinases • FGFs bind to heparan sulfate and tyrosine kinase receptors (FGFRs) • FGF binds to heparan sulfate • FGF/heparan sulfate dimer binds to a FGFR • Complexes form dimers • Signal transduction

  6. FGFRs • 7 prototypes from 4 genes • 2 or 3 immunoglobulin-like extracellular domains • Heparan sulfate binding domain • Activated through autophosphorylation • Signaling pathway includes Ras, Raf, SOS, etc.

  7. Receptor Dimerization

  8. FGFRs

  9. What Does FGF3 do in a wt Mouse? • Mouse lives (viable) • Inner ear problems • Skeletal problems (tail)

  10. Mouse Ear Development • FGF3 was thought to induce inner ear development • McKay et al. showed that FGF3 is required for correct development of inner ear, not induction of otic placode

  11. Kreisler Mutant Mice • Cannot be maintained as completely homozygous line (females do not breed and repeated outcrossing is needed to produce breeding stud males) • Develop a otic placode etc. • Inner ear is mutant

  12. FGF Expression

  13. Breast Cancer Numbers • Most frequent cancer among women, other than skin cancer • 203,500 new cases per year in U.S. • 40,000 die each year • 1 in 8 women • 5% attributed to mutated BRCA1

  14. FGF3 and Breast Cancer • Mouse Mammary Tumor Virus (MMTV) • Insertion of MMTV activates several genes including FGF3 that have been associated with breast cancer • Mixed results • Cyclin D is closely linked to FGF3

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