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Fes/ Fps Gene

Fes/ Fps Gene. Fes: Feline Sarcoma. Same as Fps: Fujinami poultry sarcoma A proto-oncogene Located in the cytoplasm Encodes a non-receptor protein-tyrosine kinase Fes/Fps and Fer (Fes-related protein) are the only members of a distinct family of kinases. Predicted Domains.

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Fes/ Fps Gene

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  1. Fes/ Fps Gene

  2. Fes: Feline Sarcoma • Same as Fps: Fujinami poultry sarcoma • A proto-oncogene • Located in the cytoplasm • Encodes a non-receptor protein-tyrosine kinase • Fes/Fps and Fer (Fes-related protein) are the only members of a distinct family of kinases

  3. Predicted Domains • Amino-terminal FCH domain • Three Coiled-coil domains • Central SH2 domain • Carboxy-terminal kinase domain

  4. FCH Domain • Unknown structure and function • Apparent affinity for microtubules • Functions of homologous FCH regions in other proteins, such as regulation of cytoskeletal rearrangements, vesicular transport, and endocytosis, could provide insight to its function

  5. Three Coiled-Coil Domains • Coiled-Coil – Quaternary protein structure formed by two or three  helices interacting with each other along their length • Negative regulation of kinase activity • Mediate oligomerization (see diagram) • Recruitment of signaling partners

  6. Hypothetical means of regulating oligomerization:Smithgall et al. 1998

  7. Central SH2 Domain • Mediates protein-protein interactions that are essential for the transforming activities of the oncogenic Fps/Fes kinase (Greer 2002) • Possible SH2 domain-interacting proteins: Bcr Abl (Kinase) FAK (Focal Adhesion Kinase)

  8. Carboxy-terminus Kinase Domain • Phosphorylates target proteins • Possible target proteins: Bcr Abl FAK

  9. Mutations in Coiled-Coil Domains Experiment: Cheng et al. 2001 • Mutants expressed in myeloid-leukemia cell lines • One bp deletion in first c-c domain: dramatic increase in kinase activity • Cells were less dependent on growth stimulus and spreading was induced

  10. Mutations in Coiled-Coil Domains Experiment: Cheng et al. 2001 • One bp mutation in the second c-c domain had no effect BUT: • Double-mutant led to reduced kinase activity

  11. Mutation – Protein Fusion Peter Greer 2002

  12. Participation in Signal Transduction Pathways • Fes/ Fps is thought to act downstream of cytokine receptors • Functions of these pathways are unknown

  13. Fes/ Fps is thought to play a role in regulating… • Cell-matrix and cell-cell adhesions • Hematopoiesis (controversial) • Cytoskeletal rearrangements • Intracellular signaling • *Bcr-Abl

  14. Fes and Bcr-Abl • Hematopoietic cells need cytokines in order to survive and grow • Bcr-Abl is an oncogene whose expression makes hematopoietic cells grow independently of cytokines • Fes expression in leukemia cells antagonizes the actions of Bcr-Abl .: one normal function of the Fes gene is to suppress a rare oncogene Lionberger and Smithgall 2000

  15. Fes acts downstream of cytokine receptors Hematopoietic cells need cytokines in order to survive and grow What will happen when the Fes gene is eliminated from an animal? Review:

  16. Hypothesis: A mouse lacking both copies of the Fes gene will not survive since hematopoiesis will not function properly.

  17. Results: • Fes-null mice were healthy and viable! • Two small problems: 1) the mice had slightly less bone marrow progenitors and circulating mature myeloid cells 2) the mice were more sensitive to Lipopolysaccharide (LPS) (~bacteria) • Proof: the Fes-null phenotypes were rescued using a wild-type Fes transgene Zirngibl et al. 2002

  18. Conclusion: • Fes is not essential for development and survival • The roles of Fes and Fer may be redundant .:What will happen when to a mouse that lacks both the Fes and Fer genes?

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