STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis.

Abstract

In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular-signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones.

• Authors: Y Sekine, O Ikeda, A Mizushima, Y Ueno, R Muromoto, A Yoshimura, Y Kanakura, K Oritani, T Matsuda
• Journal: Oncogene (Oncogene) Vol. 31 Issue 40 Pg. 4384-96 (Oct 04 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 22231445 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Phosphoproteins
• Receptors, Chemokine
• STAP2 protein, human
• Fusion Proteins, bcr-abl
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, metabolism)
• Mice
• Phosphoproteins (genetics, metabolism)
• Phosphorylation
• Protein Binding
• Receptors, Chemokine (metabolism)