A novel Stat3 binding motif in Gab2 mediates transformation of primary hematopoietic cells by the Stk/Ron receptor tyrosine kinase in response to Friend virus infection.
Friend erythroleukemia virus has long served as a paradigm for the study of the multistage progression of leukemia. Friend virus infects erythroid progenitor cells, followed by an initial polyclonal expansion of infected cells, which is driven by the activation of a naturally occurring truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Subsequently, the accumulation of additional mutations in p53 and the activation of PU.1 result in full leukemic transformation. The early stages of transformation induced by Friend virus are characterized in vitro by the Epo-independent growth of infected erythroblasts. We have shown previously that this transforming event requires the kinase activity and Grb2 binding site of Sf-Stk and the recruitment of a Grb2/Gab2 complex to Sf-Stk. Here, we demonstrate that Stat3 is required for the Epo-independent growth of Friend virus-infected cells and that the activation of Stat3 by Sf-Stk is mediated by a novel Stat3 binding site in Gab2. These results underscore a central role for Stat3 in hematopoietic transformation and describe a previously unidentified role for Gab2 in the recruitment and activation of Stat3 in response to transforming signals generated by tyrosine kinases.
Ni
Shuang
S
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, 115 Henning Building, University Park, PA 16802-3500, USA.
Zhao
Chunmei
C
Feng
Gen-Sheng
GS
Paulson
Robert F
RF
Correll
Pamela H
PH
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism; D005622:Friend murine leukemia virus / Q000378:metabolism*; D006801:Humans; D007942:Leukemia, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012192:Retroviridae Infections; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014412:Tumor Virus Infections
D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004921:Erythropoietin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases