Signal transduction and cellular functions of the TEL/ARG oncoprotein.
The TEL/ARG oncogene is formed by t(1;12)(q25;p13) reciprocal translocation and is associated with human leukemia. We have previously demonstrated that the expression of TEL/ARG in Ba/F3 cells results in prolonged viability and hyper-responsiveness to IL-3. To determine the molecular mechanisms, a series of mutants of TEL/ARG were generated, and each cDNA was expressed in Ba/F3 or CHO cells. The PNT domain in TEL and K317 in ARG were essential for both signaling and biological effects. The SH3 domain in ARG was required for hyper-responsiveness to IL-3, but not for prolonged viability. The opposite was true for the SH2 domain in ARG. Mutation of Y314 in TEL, a putative GRB2-binding site, led to reduced viability, and loss of hyper-responsiveness to IL-3. All biological functions were profoundly impaired with deletion of the C-terminus in ARG, despite maintaining high levels of its kinase activity. When expressed in CHO cells, wild-type TEL/ARG induced the formation of fillopodia, in a fashion dependent on the C-terminal portion and intact kinase activity. Thus, these results suggest several critical domains within TEL/ARG necessary for function, and indicate that the signaling pathways necessary for viability, growth factor hyper-responsiveness and cytoskeletal reorganization are likely to be separate.
Okuda
K
K
Department of Health Sciences and Preventive Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. keiko_o@koto.kpu-m.ac.jp
Oda
A
A
Sato
Y
Y
Nakayama
A
A
Fujita
H
H
Sonoda
Y
Y
Griffin
J D
JD
D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology; D006224:Cricetinae; D004318:Doxycycline / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics; D007377:Interleukin-3 / Q000494:pharmacology; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D016296:Mutagenesis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D019012:Integrin beta1; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; C426235:TEL-ARG fusion protein, human; D011505:Protein-Tyrosine Kinases; D004318:Doxycycline