c-Abl Activates Janus Kinase 2 in Normal Hematopoietic Cells

Leng, Xiaohong; Chakraborty, Sharmistha; Ma, Helen; Arlinghaus, Ralph B.

doi:10.1074/jbc.m114.554501

Cited by 10 publications

(12 citation statements)

References 55 publications

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“…We have previously shown that Jak2 kinase activity was required for the stability of Bcr-Abl by phosphorylating Tyr 177 within the Bcr portion of Bcr-Abl [ 41 ], which triggers the binding of Grb2 to pTyr 177 leading Ras pathway members associate with Bcr-Abl [ 42 ]. As Shc is also known to bind to Bcr-Abl, the interaction between Grb2 and Shc also causes Ras pathway members to bind to a second site in Bcr-Abl besides the tyrosine 177 site [ 43 ] Our previous cellular based pull down experiments and the bimolecular fluorescence complementation studies documented that Jak2 directly binds to Bcr-Abl and c-Abl through their C-terminal and kinase domains of c-Abl [ 4 , 44 ]. Bcr-Abl and c-Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 leading to its kinase activation [ 4 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

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HSP90 inhibitor AUY922 induces cell death by disruption of the Bcr-Abl, Jak2 and HSP90 signaling network complex in leukemia cells

Chakraborty

Leng

et al. 2015

Genes Cancer

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The Bcr-Abl protein is an important client protein of heat shock protein 90 (HSP90). We evaluated the inhibitory effects of the HSP90 ATPase inhibitor AUY922 on 32D mouse hematopoietic cells expressing wild-type Bcr-Abl (b3a2, 32Dp210) and mutant Bcr-Abl imatinib (IM)-resistant cell lines. Western blotting results of fractions from gel filtration column chromatography of 32Dp210 cells showed that HSP90 together with Bcr-Abl, Jak2 Stat3 and several other proteins co-eluted in peak column fractions of a high molecular weight network complex (HMWNC). Co-IP results showed that HSP90 directly bound to Bcr-Abl, Jak2, Stat 3 and Akt. The associations between HSP90 and Bcr-Abl or Bcr-Abl kinase domain mutants (T315I and E255K) were interrupted by AUY922 treatment. Tyrosine phosphorylation of Bcr-Abl showed a dose-dependent decrease in 32Dp210T315I following AUY922 treatment for 16h. AUY922 also markedly inhibited cell proliferation of both IM-sensitive 32Dp210 (IC50 =6 nM) and IM-resistant 32Dp210T315I cells (IC50 ≈6 nM) and human KBM-5R/KBM-7R cell lines (IC50 =50 nM). AUY922 caused significant G1 arrest in 32Dp210 cells but not in T315I or E255K cells. AUY922 efficiently induced apoptosis in 32Dp210 (IC50 =10 nM) and T315I or E255K lines with IC50 around 20 to 50 nM. Our results showed that Bcr-Abl and Jak2 form HMWNC with HSP90 in CML cells. Inhibition of HSP90 by AUY922 disrupted the structure of HMWNC, leading to Bcr-Abl degradation, nhibiting cell proliferation and inducing apoptosis. Thus, inhibition of HSP90 is a powerful way to inhibit not only IM-sensitive CML cells but also IM-resistant CML cells.

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Section: Discussionmentioning

confidence: 99%

“…Apoptosis assay was performed as described previously [ 44 ]. Briefly, cells were seeded in 12 well plate at 0.5×10 6 cells per well.…”

Section: Methodsmentioning

confidence: 99%

HSP90 inhibitor AUY922 induces cell death by disruption of the Bcr-Abl, Jak2 and HSP90 signaling network complex in leukemia cells

Chakraborty

Leng

et al. 2015

Genes Cancer

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“…The proliferation of cancer cells is sensitive to HSP90 inhibition using small molecules that target the ATPase activity of the chaperone (Tao et al, 2015;Wang et al, 2013a). HSP90 is likely required for the stabilization of a subset of proteins that is critical for cell proliferation.…”

Section: A Screen To Identify Chromatin Regulators Functionally Intermentioning

confidence: 99%

Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

et al. 2019

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“…Both are murine-derived cell lines dependent on IL3 for viability and growth and have been extensively used as a model system for studying transforming properties of oncogenes (27)(28)(29)(30)(31). The choice of the 32D cells over Ba/F3 cells was due to their more established origin (32)(33)(34) and availability.…”

Section: Fgfr3-tacc3 Promotes Il3 Independent Cell Growthmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Using titanium dioxide-based phosphopeptide enrichment (TiO 2 )-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it was demonstrated that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase-dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain.Implications: These results demonstrate that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target, but that phosphorylated tyrosine residues within the TACC3-derived portion are not critical for activity.

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c-Abl Activates Janus Kinase 2 in Normal Hematopoietic Cells

Cited by 10 publications

References 55 publications

HSP90 inhibitor AUY922 induces cell death by disruption of the Bcr-Abl, Jak2 and HSP90 signaling network complex in leukemia cells

HSP90 inhibitor AUY922 induces cell death by disruption of the Bcr-Abl, Jak2 and HSP90 signaling network complex in leukemia cells

Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

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