p210Bcr−Abl desensitizes Cdc42 GTPase signaling for SDF-1α-directed migration in chronic myeloid leukemia cells

Chang, Yuan-Chen; Tien, Sui Chih; Tien, Hwei‐Fang; Zhang, H; Bokoch, Gary M.; Chang, Zee-Fen

doi:10.1038/onc.2009.260

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…Furthermore, the phosphorylation status of the BCR-ABL downstream signaling molecule, STAT5b, was also diminished (Figure 3e). We then analyzed the effects of STAP-2 knockdown on tyrosine phosphorylation of STAT5 as well as CBL and VAV whose molecular weight is B100 kDa and their activation by BCR-ABL was already reported (Brehme et al, 2009;Chang et al, 2009). As shown in Figure 3f, tyrosine phosphorylation of both CBL and VAV also reduced in STAP-2-knockdown K562 cells.…”

Section: Stap-2 Enhances Bcr-abl Activitymentioning

confidence: 59%

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

et al. 2012

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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 up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-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. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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Section: Stap-2 Enhances Bcr-abl Activitymentioning

confidence: 59%

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

et al. 2012

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“…Further research demonstrates that Bcr-Abl oncoprotein binds directly to activators of the Ras signaling pathway and effector molecules of RalA, such as CDC42 and Grb2 in ras signaling pathway, play a major role in Bcr-Abl-induced leukemogenesis [31],[32],[33]. Therefore, RalA, as one small GTPase molecule of the Ras network, might also play an important role in oncogenesis of CML.…”

Section: Discussionmentioning

confidence: 98%

miR-181a Post-Transcriptionally Downregulates Oncogenic RalA and Contributes to Growth Inhibition and Apoptosis in Chronic Myelogenous Leukemia (CML)

Jia

Li²,

Zhu³

et al. 2012

PLoS ONE

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MicroRNAs (miRNAs) are a class of short RNAs that regulate gene expression through either translational repression or mRNA cleavage. miRNA-181a (miR-181a), one of the many miRNAs conserved among vertebrates, is differentially expressed in a variety of leukemia. However, its function in leukemia, particularly chronic myelogenous leukemia (CML), is poorly understood. Here we have reported the identification of miR-181a targets by combining TargetScan software prediction and expression profiling through overexpression of miR-181a mimic in leukemic K562 cells. Four overlapping genes were found to be the likely targets of miR-181a. Among the four genes, RalA is a downstream molecule of bcr-abl fusion protein in ras signaling pathway. However, its role in CML remains elusive. Luciferase reporter and Western blot assays confirmed that RalA is a direct target of miR-181a. overexpression of miR-181a effectively suppresses cell growth and induces G2-phase arrest and apoptosis partially by targeting RalA in leukemic K562 cells. Using the KEGG database combined with recent publications, downstream signaling pathway of RalA was graphed by cytoscape software. Therefore, our study is the first to report that RalA is directly regulated by miR-181a and plays an important role in CML. The approach of computational prediction combined with expression profiling might be valuable for the identification of miRNA targets in animal.

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“…Cdc42 belongs to the large Rho family of GTPases essential for neurite outgrowth (Kozma et al 1997). As Rho proteins are key regulators of the cytoskeleton and ABL kinases are required at least in part for activation of Cdc42 (Burton et al 2005;Chang et al 2009), there might be important link between alteration in neuritogenesis in the brain and peripheral blood biomarkers. Ubiquitously expressed ABL1 tyrosine kinase and Cdc42 protein might represent potential diagnostic and predictive biomarkers for autistic patients.…”

Section: Potential Biomarkers In Autismmentioning

confidence: 99%

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

et al. 2015

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Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

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p210Bcr−Abl desensitizes Cdc42 GTPase signaling for SDF-1α-directed migration in chronic myeloid leukemia cells

Cited by 17 publications

References 36 publications

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

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

miR-181a Post-Transcriptionally Downregulates Oncogenic RalA and Contributes to Growth Inhibition and Apoptosis in Chronic Myelogenous Leukemia (CML)

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

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