Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation

Jeffrey D. Ceci, Christos P. Patriotis, Christos Tsatsanis, Antonios M. Makris, Robert Kovatch, Deborah A. Swing, Nancy A. Jenkins, Philip N. Tsichlis, Neal G. Copeland

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Provirus insertion in the last intron of the Tpl-2 gene in retrovirus- induced rat T-cell lymphomas results in the enhanced expression of a carboxy- terminally truncated Tpl-2 kinase. Here we show that the truncated protein exhibits an approximately sevenfold higher catalytic activity and is two- to threefold more efficient in activating the MAPK and SAPK pathways relative to the wild-type protein. The truncated Tpl-2 protein and a GST fusion of the Tpl-2 carboxy-terminal tail interact when coexpressed in Sf9 cells. Their interaction down-regulates the kinase activity of the truncated protein suggesting that tail-directed intramolecular interactions regulate the Tpl-2 kinase. Tpl-2 transgenic mice expressing the wild-type protein from the proximal Lck promoter fail to show a biological phenotype, whereas mice expressing the truncated protein develop large.cell lymphoblastic lymphomas of T-cell origin. These results show that Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation.

Original languageEnglish (US)
Pages (from-to)688-700
Number of pages13
JournalGenes and Development
Volume11
Issue number6
DOIs
StatePublished - Mar 15 1997

Keywords

  • MAPK
  • oncogenesis
  • protein kinase
  • SAPK
  • Tpl-2/Cot proto-oncogene
  • transgenic mice

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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