Activation of STAT5 triggers proliferation and contributes to anti-apoptotic signalling mediated by the oncogenic Xmrk kinase.
Extensive studies of primary tumors and tumor derived cell lines revealed that inappropriate activation of specific STATs (particularly of STAT3 and STAT5) occurs with high frequency in a wide variety of human cancers. We reported recently that the melanoma inducing EGFR-related receptor Xmrk specifically induces constitutive activation of STAT5 in fish melanoma cells. However, little is known about the role of STAT5 in solid tumours in general and its function in melanoma in particular. Recent examinations suggest that activated STAT signalling participates in oncogenesis by stimulating cell proliferation and preventing apoptosis. As an initial approach to understanding the consequences of Xmrk induced STAT5 signalling we used the well characterized pro B-cell line Ba/F3 as a sensitive system to analyse mitogenic as well as anti-apoptotic signalling. We identified STAT5 activation as being involved in both growth and survival signalling triggered by the Xmrk kinase possibly due to STAT5 induced expression of pim-1 and bcl-x. We also found a new mechanism of activation of STAT5 by receptor tyrosine kinases, whereby direct interaction of the receptor kinase domain with the STAT protein in a phosphotyrosine independent way led to activation of STAT5 in terms of DNA binding and target gene expression.
Morcinek
Jessica C
JC
Department of Physiological Chemistry I, Biocenter (Theodor-Boveri Institut), University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Weisser
Christin
C
Geissinger
Eva
E
Schartl
Manfred
M
Wellbrock
Claudia
C
D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology*; D019281:Dimerization; D066246:ErbB Receptors / Q000502:physiology; D029941:Fish Proteins; D006801:Humans; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D019000:Phosphotyrosine / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D051573:Proto-Oncogene Proteins c-pim-1; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D029941:Fish Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051020:bcl-X Protein; D019000:Phosphotyrosine; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C077101:Xmrk protein, Xiphophorus; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D020928:Mitogen-Activated Protein Kinases