A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation.
Lck is a Src family protein tyrosine kinase and is expressed predominantly in T cells. Aberrant expression or activation of Lck kinase has been reported in both lymphoid and nonlymphoid malignancies. However, the mechanisms underlying Lck-mediated oncogenesis remain largely unclear. In this report, we establish a tetracycline-inducible system to study the biochemical and biological effects of a constitutively active Lck mutant with a point mutation at the negative regulatory tyrosine. Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA-binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells. The active Lck kinase interacts with STAT5b in cells, suggesting that Lck may directly phosphorylate STAT5b. Expression of the constitutively active Lck mutant in interleukin-3 (IL-3)-dependent BaF3 cells promotes cell proliferation. In addition, the active Lck kinase protects BaF3 cells from IL-3 withdrawal-induced apoptotic death and leads to IL-3-independent growth. These transforming properties of the oncogenic Lck kinase can be further augmented by expression of exogenous wild-type STAT5b but attenuated by a dominant-negative form of STAT5b. All together, our results suggest the potential involvement of STAT5b in Lck-mediated cellular transformation.
Shi
Mingjian
M
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.
Cooper
John C
JC
Yu
Chao-Lan
CL
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D007377:Interleukin-3 / Q000172:deficiency; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D050799:STAT5 Transcription Factor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D013752:Tetracycline