The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors.
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.
Franco
Mélanie
M
CRBM, CNRS FRE2593, 1919 Route de Mende, 34293 Montpellier Cedex 05, France. Serge.Roche@crbm.cnrs.fr.
Furstoss
Olivia
O
Simon
Valérie
V
Benistant
Chrsitine
C
Hong
Wan Jing
WJ
Roche
Serge
S
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008934:Mitogens / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011506:Proteins; C485627:TOM1 protein, mouse; C447618:Tom1L1 protein, mouse; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases