EGFR-independent activation of ERK1/2 mediates growth inhibition by a PTPase antagonizing K-vitamin analog

Siddhartha Karr, Takahito Adachi, Brian I. Carr

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The K-vitamin analog Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone] is a potent cell growth inhibitor in vitro and in vivo, likely due to arylation of enzymes containing a catalytic cysteine. This results in inhibition of protein tyrosine phosphatase (PTPase) activity with resultant hyperphosphorylation of EGF receptors (EGFR) and ERK1/2 protein kinases, which are downstream to EGFR in the MAPK pathway. We used NR6 fibroblast cells, which lack endogenous EGFR and its variant cells transfected with different EGFR mutants to assess the contribution of the EGFR-mediated signaling pathway to Cpd 5-mediated ERK activation and cell growth inhibition. Cpd 5 treatment resulted in enhanced phosphorylation of EGFR at carboxyl-terminal tyrosines. This phosphorylation and activation of EGFR were found to be necessary neither for growth inhibition nor for the activation of the downstream kinases ERK1/2, since both occurred in EGFR-devoid mutant cells. U0126 and PD 098059, specific inhibitors of MEK1/2, the ERK1/2 kinases, antagonized both cell growth inhibition and ERK1/2 phosphorylation mediated by Cpd5. Cpd 5 was also found to inhibit ERK1/2 phosphatase(s) activity in lysates from all the cells tested, irrespective of their EGFR status. These results show that EGFR-independent ERK1/2 phosphorylation was involved in the mechanism of Cpd5 mediated growth inhibition. This is likely due to the observed antagonism of ERK phosphatase activity. A candidate PTPase was found to be Cdc25A, a recently identified ERK phosphatase.

Original languageEnglish
Pages (from-to)356-364
Number of pages9
JournalJournal of Cellular Physiology
Volume190
Issue number3
DOIs
Publication statusPublished - 2002

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Protein Tyrosine Phosphatases
Vitamin K
Chemical activation
Growth
Phosphorylation
Phosphoric Monoester Hydrolases
Mitogen-Activated Protein Kinase 3
Cell growth
ErbB Receptors
Growth Inhibitors
Mercaptoethanol
Fibroblasts
Protein Kinases
Cysteine
Tyrosine
Phosphotransferases
Cells

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

EGFR-independent activation of ERK1/2 mediates growth inhibition by a PTPase antagonizing K-vitamin analog. / Karr, Siddhartha; Adachi, Takahito; Carr, Brian I.

In: Journal of Cellular Physiology, Vol. 190, No. 3, 2002, p. 356-364.

Research output: Contribution to journalArticle

Karr, Siddhartha ; Adachi, Takahito ; Carr, Brian I. / EGFR-independent activation of ERK1/2 mediates growth inhibition by a PTPase antagonizing K-vitamin analog. In: Journal of Cellular Physiology. 2002 ; Vol. 190, No. 3. pp. 356-364.
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