ABSTRACT
The oncogenic JAK2V617F mutation is found in myeloproliferative neoplasms (MPNs) and is believed to be critical for leukemogenesis. Here we show that JAK2V617F requires an intact SH2 domain for constitutive activation of downstream signaling pathways. In addition, there is a strict requirement of cytokine receptor expression for the activation of this oncogene. Further analysis showed that the SH2 domain mutation did not interfere with JAK2 membrane distribution. However, coimmunoprecipitated experiments revealed a role for the SH2 domain in the aggregation and cross-phosphorylation of JAK2V617F at the cell membrane. Forced overexpression of cytokine receptors could rescue the JAK2V617F SH2 mutant supporting a critical role of JAK2V617F abundance for constitutive activation. However, under physiologic cytokine receptor expression the SH2 domain is absolutely necessary for oncogenic JAK2V617F activation. This is demonstrated in a bone marrow transplantation model, in which an intact SH2 domain in JAK2V617F is required for the induction of an MPN-like disease. Thus, our results points to an indispensable role of the SH2 domain in JAK2V617F-induced MPNs.
Subject(s)
Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/enzymology , src Homology Domains , Animals , Cell Line, Tumor , Cell Proliferation , Humans , Mice , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , PhosphorylationABSTRACT
Persistently activated Stat3 is found in many different cancers, including approximately 60% of breast tumors. Here, we demonstrate that a constitutively activated Stat3 transforms immortalized human mammary epithelial cells and that this oncogenic event requires the activity of matrix metalloproteinase-9 (MMP-9). By immunohistochemical analysis, we observe a positive correlation between strong MMP-9 expression and tyrosine phosphorylated Stat3 in primary breast cancer specimens. These results demonstrate a relationship between activated Stat3 and MMP-9 in breast oncogenesis.