v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells.
The v-Abl oncogene activates Jak-Stat signaling during transformation of pre-B cells in mice. Disrupting Jak activation by deleting the Jak binding domain of v-Abl or by expressing a dominant-negative Jak1 decreases v-Abl transformation efficiency. As SOCS-1 is a known potent inhibitor of Jak kinases, the mechanism by which v-Abl bypasses ... SOCS-1 regulation to constitutively activate Jak kinases was investigated. SOCS-1 is expressed in v-Abl-transformed cells but is unable to inhibit v-Abl-mediated Jak-Stat signaling. In v-Abl transformants, SOCS-1 can inhibit cytokine signals, but it is more efficient at doing so when the cells are treated with STI571, an Abl kinase inhibitor. Downstream effects of v-Abl signaling include phosphorylation of SOCS-1 on nontyrosine residues, disruption of the interaction between SOCS-1 and the Elongin BC complex, and inhibition of SOCS-1-mediated proteasomal targeting of activated Jaks. These findings reveal a mechanism by which Jak-dependent oncogenes may bypass SOCS-1 inhibition.
Mesh Terms:
Animals, B-Lymphocytes, Bone Marrow Cells, Carrier Proteins, Cell Transformation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mutation, Oncogene Proteins v-abl, Protein-Tyrosine Kinases, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins
Animals, B-Lymphocytes, Bone Marrow Cells, Carrier Proteins, Cell Transformation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mutation, Oncogene Proteins v-abl, Protein-Tyrosine Kinases, Repressor Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins
Mol. Cell
Date: Aug. 13, 2004
PubMed ID: 15304214
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