Phosphorylation of three regulatory serines of Tob by ErK1 and ErK2 is required for Ras-mediated cell proliferation and transformation

Toru Suzuki, Junko K-Tsuzuku, Rieko Ajima, Takahisa Nakamura, Yutaka Yoshida, Tadashi Yamamoto

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)


tob is a member of an emerging family of genes with antiproliferative function. Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. Oncogenic Ras-induced transformation and growth-factor-induced cell proliferation are efficiently suppressed by mutant Tob that carries alanines but not glutamates, mimicking phosphoserines, at these sites. Wild-type Tob inhibits cell growth when the three serine residues are not phosphorylated but is less inhibitory when the serines are phosphorylated. Because growth of Rb-deficient cells was not affected by Tob, Tob appears to function upstream of Rb. Intriguingly, cyclin D1 expression is elevated in serum-starved tob-/- cells. Reintroduction of wild-type Tob and mutant Tob with serine-to-alanine but not to glutamate mutations on the Erk phosphorylation sites in these cells restores the suppression of cyclin D1 expression. Finally, the S-phase population was significantly increased in serum-starved tob-/- cells as compared with that in wild-type cells. Thus, Tob inhibits cell growth by suppressing cyclin D1 expression, which is canceled by Erk1- and Erk2-mediated Tob phosphorylation. We propose that Tob is critically involved in the control of early G1 progression.

Original languageEnglish
Pages (from-to)1357-1370
Number of pages14
JournalGenes and Development
Issue number11
Publication statusPublished - 2002 Jun 1
Externally publishedYes


  • Cell cycle entry
  • Ras/MAPK pathway
  • Tob phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


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