A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis

Xiaoxue Qiu, Guijie Guo, Ke Chen, Masaki Kashiwada, Brian Druker, Paul B. Rothman, Ji Long Chen

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)547-558
Number of pages12
JournalNeoplasia (United States)
Volume14
Issue number6
DOIs
StatePublished - Jun 2012

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Janus Kinases
Carcinogenesis
Tyrosine
Phosphorylation
Protein-Tyrosine Kinases
Suppressor of Cytokine Signaling Proteins
Transducers
bcl-X Protein
Cytokines
K562 Cells
Oncogene Proteins
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Nude Mice
Bone Marrow
Apoptosis
Mutation

ASJC Scopus subject areas

  • Cancer Research

Cite this

A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis. / Qiu, Xiaoxue; Guo, Guijie; Chen, Ke; Kashiwada, Masaki; Druker, Brian; Rothman, Paul B.; Chen, Ji Long.

In: Neoplasia (United States), Vol. 14, No. 6, 06.2012, p. 547-558.

Research output: Contribution to journalArticle

Qiu, X, Guo, G, Chen, K, Kashiwada, M, Druker, B, Rothman, PB & Chen, JL 2012, 'A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis', Neoplasia (United States), vol. 14, no. 6, pp. 547-558. https://doi.org/10.1596/neo.12230
Qiu, Xiaoxue ; Guo, Guijie ; Chen, Ke ; Kashiwada, Masaki ; Druker, Brian ; Rothman, Paul B. ; Chen, Ji Long. / A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis. In: Neoplasia (United States). 2012 ; Vol. 14, No. 6. pp. 547-558.
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