Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation.
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.
Ceci
J D
JD
National Cancer Institute-Frederick Cancer Research Facility and Development Center, Maryland 21702, USA.
Patriotis
C P
CP
Tsatsanis
C
C
Makris
A M
AM
Kovatch
R
R
Swing
D A
DA
Jenkins
N A
NA
Tsichlis
P N
PN
Copeland
N G
NG
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D066298:In Vitro Techniques; D007438:Introns; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics / Q000821:virology; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011519:Proto-Oncogenes; D011533:Proviruses / Q000235:genetics; D051381:Rats; D012192:Retroviridae Infections / Q000201:enzymology / Q000235:genetics / Q000821:virology; D014412:Tumor Virus Infections / Q000201:enzymology / Q000235:genetics / Q000821:virology
D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; C080356:Map3k8 protein, rat