Activation of STAT5 triggers proliferation and contributes to anti-apoptotic signalling mediated by the oncogenic Xmrk kinase

Abstract

Extensive studies of primary tumors and tumor derived cell lines revealed that inappropriate activation of speci®c STATs (particularly of STAT3 and STAT5) occurs with high frequency in a wide variety of human cancers. We reported recently that the melanoma inducing EGFRrelated receptor Xmrk speci®cally induces constitutive activation of STAT5 in ®sh 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 identi®ed 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.

Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+central memory T cells

“…The results showed a significant increase in the forkhead box O3a (FOXO3a) transcriptional target proapoptotic genes, including Bim (25), FasL (26), and genes involved in cell cycle regulation, including GADD45a (27) and p130, a member of the retinoblastoma family (28) in the T EM subset. Furthermore, the RT-PCR data confi rmed the up-regulation of the survival gene CD27 and the antiapoptotic PIM-2 kinase, with the latter being regulated by the STAT5a cascade in T CM (29). These results validated our gene array data and further suggested the involvement of STAT5a and FOXO3a signaling pathways in mediating the survival of T CM .…”

Melanoma development and pigment cell transformation in xiphophorus

“…Costimulation by synergistic growth factors thereby leads to prolongation of MAP kinase activity, which when induced by a single growth factor alone, is almost back to basal level after 90 minutes (Bohm et al, 1995). Activation of the Xmrk kinase when expressed in murine melanocytes leads to complete suppression of melanocyte differentiation, enhanced proliferation, and induction of a transformed phenotype (Wellbrock et al, 2002). In such dedifferentiated cells, MAP kinase activation induced by the receptor was strong and sustained comparable to the situation in fish.…”

Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors

“…For example, its activation is required for Ros-induced cell transformation, 42 and it also contributes to the mitogenic signaling from the oncogenic Xmrk. 43,44 Studies in chicken B cells suggest that it has a role in proliferation as well as survival Hyperproliferative pathways from truncated G-CSF receptors J Gits et al signaling from the full-length G-CSF-R, 45 whereas others have shown that PI 3-kinase is activated by G-CSF and correlates with inhibition of apoptosis. 14 Furthermore, one of the key signaling molecules downstream of PI 3-kinase, Akt, has been shown to be activated in a sustained manner by truncated G-CSF-Rs.…”

“…52 In addition, STAT5 appears to be essential for the myelo-and lymphoproliferative disease induced by TEL-JAK2 fusions, 54 and is also required for cell cycle progression, survival and leukemogenesis induced by BCR-ABL. 55,56 Potential roles in other cancers have also been identified, including melanoma 44 and mammary cancer. 57 By corollary, expression of constitutively active forms of STAT5 has been shown to result in enhanced proliferation of myeloid cell lines 38 and of hematopoietic cells in vivo, 58 which we have recently confirmed.…”

“…For example, the full mitogenic signaling potency from the oncogenic Xmrk kinase is apparently also mediated by PI 3-kinase, MAPK and STAT5 pathways. 43,44 The challenge remains to delineate the exact contribution of each of these pathways to the transformation process at the molecular level, which is finally become a reality using microarray and other technologies. …”