Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL.

Matsuguchi, Tetsuya; Inhorn, Roger C.; Carlesso, Nadia; Xu, Gang; Druker, Brian J.; Griffin, James D.

doi:10.1002/j.1460-2075.1995.tb06999.x

Cited by 163 publications

(137 citation statements)

References 33 publications

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“…Extensive studies over the years have established that the constitutively activated tyrosine kinase activity of BCR-ABL promotes leukemic transformation by activating multiple downstream mitogenic cascades (24). Several signaling elements have been shown to be regulated by BCR-ABL, including the Ras-GAP (25), the Shc oncoprotein (26), the tyrosine phosphatase SHP-2 and phosphatidylinositol polyphosphate 5 ¶-phosphatase SHIP (27), the c-CBL (28) and Vav (29) proto-oncogene products (28), the transcriptional activator Stat5 (30,31), and the PI3K/Akt signaling pathway (32). In addition, mTOR has been recently implicated as a downstream effector of BCR-ABL (33 -35).…”

Section: Discussionmentioning

confidence: 99%

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Yoon

Giafis²,

Smith³

et al. 2006

Molecular Cancer Therapeutics

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Arsenic trioxide (As 2 O 3 ) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL -expressing cells with As 2 O 3 , there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr 421 and Ser 424 and is activated in an As 2 O 3 -inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/ activated in an As 2 O 3 -inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser 235 /Ser 236 and Ser 240 /Ser 244 to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia -derived cell lines with As 2 O 3 also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr 37 /Thr 46 and Thr 70 , sites required for its deactivation and its dissociation from the eukaryotic initiation factor 4E complex to allow cap-dependent mRNA translation. In studies to determine the functional relevance of this pathway, we found that inhibition of mTOR and downstream cascades enhances induction of apoptosis by As 2 O 3 . Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As 2 O 3 -mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, our data show that the mTOR/p70S6K pathway is activated in a negative feedback regulatory manner in response to As 2 O 3 in BCR-ABL -transformed cells and plays a key regulatory role in the induction of anti-leukemic responses.

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Section: Discussionmentioning

confidence: 99%

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Yoon

Giafis²,

Smith³

et al. 2006

Molecular Cancer Therapeutics

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“…After growth receptor ligation, Shc, a Src homology (SH)-2 (SH2)-domain containing protein, becomes associated with the c-terminus of the growth factor receptor (Matsuguchi et al, 1994, Inhorn et al, 1995, Okuda et al, 1999. Shc recruits the GTP-exchange complex growth factor receptor bound-2 (Grb2)/son of sevenless exchange (Sos) proteins resulting in the loading of membrane bound Ras with GTP (Tauchi et al, 1994, Lanfrancone et al, 1995.…”

Section: Overview Of the Pi3k/pten/akt/mtor And Raf/mek/erk Pathways mentioning

confidence: 99%

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

McCubrey

Sokolosky

Lehmann

et al. 2008

Advances in Enzyme Regulation

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The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21 Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also in...

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“…The membrane proximal intracellular portion of the receptor till amino-acid number 589, that includes the Box 1 region, was shown to be necessary and su cient for DNA synthesis mediated by several of these cytokines including IL-3 (Sato et al, 1993;Tian et al, 1996). This region was also found to be required for the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. Following cytokineinduced hetero-dimerization, this region of the receptor was found to bind to multiple signal-transducing proteins, which include JAKs, STATs, c-Src, phosphotidylinositol-3 kinase as well as Vav (Quelle et al, 1994;Jaster et al, 1997;Yoshimura et al, 1995Yoshimura et al, , 1998Rao and Mufson, 1995;Matsuguchi et al, 1995). The membrane distal domain of the receptor, spanning amino acids 589 ± 881, was shown to be required for growth inhibition that can be induced by some of the cytokines.…”

Section: Interleukin-3 (Il-3) and Its Receptor (Il3-r)mentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of di erent cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/ growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus.

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Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL.

Cited by 163 publications

References 33 publications

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

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