The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation.
We recently reported that the ETV6/FLT3 fusion protein conferred interleukin-3-independent growth on Ba/F3 cells. The present study has been conducted to assess role of the juxtamembrane domain of FLT3 for signal transduction and cell transformation. The wild-type ETV6/FLT3 fusion protein in transfected cells was a constitutively activated tyrosine kinase that led to up-regulation of PIM-1 and activations of STAT5, AKT, and MAPK. Deletion of the juxtamembrane domain abrogated interleukin-3-independent growth of the transfected cells and PIM-1 up-regulation, whereas it retained compatible levels of phosphorylations of STAT5, AKT, and MAPK. Further deletion of N-terminal region of the tyrosine kinase I domain of FLT3 completely abolished these phosphorylations. Our data indicate that the juxtamembrane domain of FLT3 in ETV6/FLT3 fusion protein is critical for cell proliferation and PIM-1 up-regulation that might be independent of a requirement for signaling through STAT5, MAPK, and AKT pathways.
Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo, Japan.
Hoang Anh
HA
Vu
Phan Thi
PT
Xinh
Yasuhiko
Y
Kano
Katsushi
K
Tokunaga
Yuko
Y
Sato
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D051573:Proto-Oncogene Proteins c-pim-1; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D051941:fms-Like Tyrosine Kinase 3; D000097764:ETS Translocation Variant 6 Protein; C494092:STAT5A protein, human; C497970:FLT3 protein, human