A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis.
Suppressors of cytokine signaling 1 and 3 (SOCS-1 and SOCS-3) are inhibitors of the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) pathway and function in a negative feedback loop during cytokine signaling. Abl transformation is associated with constitutive activation of JAK/STAT-dependent signaling. However, the mechanism by which ... Abl oncoproteins bypass SOCS inhibitory regulation remains poorly defined. Here, we demonstrate that coexpression of Bcr-Abl with SOCS-1 or SOCS-3 results in tyrosine phosphorylation of these SOCS proteins. Interestingly, SOCS-1 is highly tyrosine phosphorylated in one of five primary chronic myelogenous leukemia samples. Bcr-Abl-dependent tyrosine phosphorylation of SOCS-1 and SOCS-3 occurs mainly on Tyr 155 and Tyr 204 residues of SOCS-1 and on Tyr 221 residue of SOCS-3. We observed that phosphorylation of these SOCS proteins was associated with their binding to Bcr-Abl. Bcr-Abl-dependent phosphorylation of SOCS-1 and SOCS-3 diminished their inhibitory effects on the activation of JAK and STAT5 and thereby enhanced JAK/STAT5 signaling. Strikingly, disrupting the tyrosine phosphorylation of SOCS-1 or SOCS-3 impaired the expression of Bcl-X(L) protein and sensitized K562 leukemic cells to undergo apoptosis. Moreover, selective mutation of tyrosine phosphorylation sites of SOCS-1 or SOCS-3 significantly blocked Bcr-Abl-mediated tumorigenesis in nude mice and inhibited Bcr-Abl-mediated murine bone marrow transformation. Together, these results reveal a mechanism of how Bcr-Abl may overcome SOCS-1 and SOCS-3 inhibition to constitutively activate the JAK/STAT-dependent signaling, and suggest that Bcr-Abl may critically requires tyrosine phosphorylation of SOCS-1 and SOCS-3 to mediate tumorigenesis when these SOCS proteins are present in cells.
Mesh Terms:
Animals, Apoptosis, Cell Transformation, Neoplastic, Female, Fusion Proteins, bcr-abl, Gene Expression, Humans, Janus Kinase 1, Janus Kinase 2, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Mice, Nude, Mutation, Phosphorylation, Protein Binding, STAT Transcription Factors, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Transcription Factors, Tyrosine
Animals, Apoptosis, Cell Transformation, Neoplastic, Female, Fusion Proteins, bcr-abl, Gene Expression, Humans, Janus Kinase 1, Janus Kinase 2, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Mice, Nude, Mutation, Phosphorylation, Protein Binding, STAT Transcription Factors, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Transcription Factors, Tyrosine
Neoplasia
Date: Jun. 01, 2012
PubMed ID: 22787435
View in: Pubmed Google Scholar
Download Curated Data For This Publication
152007
Switch View:
- Interactions 3