The Adaptor Protein Tom1L1 Is a Negative Regulator of Src Mitogenic Signaling Induced by Growth Factors
| Autor: | Mélanie Franco, Wan Jing Hong, Serge Roche, Valérie Simon, Olivia Furstoss, Chrsitine Benistant |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Receptor complex
Platelet-derived growth factor chemistry.chemical_compound Mice FYN Animals Humans Receptors Platelet-Derived Growth Factor Phosphorylation Growth Substances Molecular Biology Cells Cultured Adaptor Proteins Signal Transducing Platelet-Derived Growth Factor DNA synthesis biology Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Proteins Cell Biology Articles DNA Actins Cell biology Protein Structure Tertiary src-Family Kinases chemistry Mutation biology.protein Signal transduction Mitogens Platelet-derived growth factor receptor Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Popis: | The Src family of protein-tyrosine kinases (SFK) play important roles in mitogenesis and morphological changes induced by growth factors. The involved substrates are, however, ill defined. Using an antiphosphotyrosine antibody to screen tyrosine-phosphorylated cDNA expression library, we have identified Tom1L1, an adaptor protein of the Tom1 family and a novel substrate and activator of the SFK. Surprisingly, we found that Tom1L1 does not promote DNA synthesis induced by Src. Furthermore, we report that Tom1L1 negatively regulates SFK mitogenic signaling induced by platelet-derived growth factor (PDGF) through modulation of SFK-receptor association: (i) Tom1L1 inhibits DNA synthesis induced by PDGF; (ii) inhibition is overcome by c-myc expression or p53 inactivation, two regulators of SFK mitogenic function; (iii) Src or Fyn coexpression overrides Tom1L1 mitogenic activity; (iv) overexpression of the adaptor reduces Src association with the receptor; and (v) protein inactivation potentiates receptor complex formation, allowing increased SFK activation and DNA synthesis. However, Tom1L1 affects neither DNA synthesis induced by the constitutively active allele SrcY527F nor SFK-regulated actin assembly induced by PDGF. Finally, overexpressed Tom1 and Tom1L2 also associate with Src and affected mitogenic signaling in agreement with some redundancy among members of the Tom1 family. We concluded that Tom1L1 defines a novel mechanism for regulation of SFK mitogenic signaling induced by growth factors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|