Phosphatidylinositol 3-Kinase p85α Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences

Ren, Shuyue; Bolton, Elisabeth; Mohi, M. Golam; Morrione, Andrea; Neel, Benjamin G.; Skórski, Tomasz

doi:10.1128/mcb.25.18.8001-8008.2005

Cited by 25 publications

(21 citation statements)

References 61 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Broad-spectrum inhibitors of PI3K catalytic subunits, such as LY294002 or wortmannin, block BCR-ABL transformation, but the effects of targeting specific catalytic isoforms have not been reported (7,9). Among regulatory isoforms, p85α appears to be essential for CML cell survival (8,11). However, we found that targeted deletion of the mouse gene Pik3r1, encoding p85α as well as p55α and p50α, caused only partial impairment of leukemic lymphoid colony formation (CFU-pre-B) and leukemogenesis (9).…”

Section: Introductionmentioning

confidence: 99%

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Kharas¹,

Janes²,

Scarfone³

et al. 2008

J. Clin. Invest.

138

View full text Add to dashboard Cite

Some cases of pre-B cell acute lymphoblastic leukemia (pre-B-ALL) are caused by the Philadelphia (Ph) chromosome-encoded BCR-ABL oncogene, and these tend to have a poor prognosis. Inhibitors of the PI3K/AKT pathway reduce BCR-ABL-mediated transformation in vitro; however, the specific PI3K isoforms involved are poorly defined. Using a murine model of Ph + pre-B-ALL, we found that deletion of both Pik3r1 and Pik3r2, genes encoding class IA PI3K regulatory isoforms, severely impaired transformation. BCR-ABL-dependent pre/pro-B cell lines could be established at low frequency from progenitors that lacked these genes, but the cells were smaller, proliferated more slowly, and failed to cause leukemia in vivo. These cell lines displayed nearly undetectable PI3K signaling function and were resistant to the PI3K inhibitor wortmannin. However, they maintained activation of mammalian target of rapamycin (mTOR) and were more sensitive to rapamycin. Treatment with rapamycin caused feedback activation of AKT in WT cell lines but not PI3K-deficient lines. A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19 + CD34 + Ph + ALL leukemia cells treated with the ABL kinase inhibitor imatinib. Our findings provide mechanistic insights into PI3K dependency in oncogenic networks and provide a rationale for targeting class IA PI3K, alone or together with mTOR, in the treatment of Ph + ALL.

show abstract

Section: Introductionmentioning

confidence: 99%

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Kharas¹,

Janes²,

Scarfone³

et al. 2008

J. Clin. Invest.

138

View full text Add to dashboard Cite

show abstract

“…Comparison of phospho-Ser473 Akt in cells with and without NPM-ALK expression revealed no significant changes in Akt activity among the cell lines, suggesting that activity per se is not responsible for changes in Akt stability. Note that NPM-ALK expression is associated with increased Akt activity via a direct activation of PI3 kinase [25,26], although IL-3 was always included in our experiments which itself activates Akt [27].…”

Section: Discussionmentioning

confidence: 99%

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Theodoraki

Kunjappu

Sternberg

et al. 2007

Experimental Cell Research

View full text Add to dashboard Cite

Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3, for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPMALK, which also correlates with increased Akt stability.

show abstract

“…is a heterodimer phospholipid kinase consisting of a 110-kDa catalytic subunit (p110) and a 85-kDa regulatory subunit (p85), which has been shown to associate with activated tyrosine kinases, including integrin-associated FAK and Shc (36,37). We investigated whether FAK and Shc play synergistic roles in cooperation with PI3K to form FAK⅐Shc⅐PI3K complexes in MG63 cells in response to OSS.…”

Section: Fak and Shc Play Synergistic Roles To Form Heteromeric Complmentioning

confidence: 99%

Oscillatory Flow-induced Proliferation of Osteoblast-like Cells Is Mediated by αvβ3 and β1 Integrins through Synergistic Interactions of Focal Adhesion Kinase and Shc with Phosphatidylinositol 3-Kinase and the Akt/mTOR/p70S6K Pathway

Lee

Chang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Interstitial flow in and around bone tissue is oscillatory in nature and affects the mechanical microenvironment for bone cell growth and formation. We investigated the role of oscillatory shear stress (OSS) in modulating the proliferation of human osteoblast-like MG63 cells and its underlying mechanisms. Application of OSS (0.5 ؎ 4 dynes/cm 2 ) to MG63 cells induced sustained activation of phosphatidylinositol 3-kinase (PI3K)/ Akt/mTOR/p70S6K (p70S6 kinase) signaling cascades and hence cell proliferation, which was accompanied by increased expression of cyclins A and D1, cyclin-dependent protein kinases-2, -4, and -6, and bone formation-related genes (c-fos, Egr-1, and Cox-2) and decreased expression of p21 CIP1 and p27 KIP1. OSS-induced activation of PI3K/Akt/mTOR/p70S6K and cell proliferation were inhibited by specific antibodies or small interference RNAs of ␣ v ␤ 3 and ␤ 1 integrins and by dominant-negative mutants of Shc (Shc-SH2) and focal adhesion kinase (FAK) (FAK(F397Y)). Co-immunoprecipitation assay showed that OSS induces sustained increases in association of Shc and FAK with ␣ v ␤ 3 and ␤ 1 integrins and PI3K subunit p85, which were abolished by transfecting the cells with FAK(F397Y) or Shc-SH2. OSS also induced sustained activation of ERK, which was inhibited by the specific PI3K inhibitor LY294002 and was required for OSS-induced activation of mTOR/p70S6K and proliferation in MG63 cells. Our findings provide insights into the mechanisms by which OSS induces osteoblast-like cell proliferation through activation of ␣ v ␤ 3 and ␤ 1 integrins and synergistic interactions of FAK and Shc with PI3K, leading to the modulation of downstream ERK and Akt/ mTOR/p70S6K pathways.Mechanical loading is critical for the formation of new bone (1-3). During dynamic and periodic loading of intact bone, the reciprocating flow of interstitial fluid through the canaliculi generates oscillatory shear stress (OSS), 3 which is detected by osteocytes in the canaliculi and osteoblasts lining the endosteal and periosteal surfaces of bone (4, 5). Stimulation of osteocytes by fluid shear stress induces their release of osteoblastic factors, which are transferred via gap junctions of the osteocyte-interconnecting network to induce osteoblast recruitment and hence bone growth (4, 6). There is increasing evidence that fluid shear stress regulates signaling, gene expression, and differentiation in osteocytes and osteoblasts (4 -9). Recent studies using flow channels have demonstrated that application of steady fluid shear stress to osteoblasts induces cell proliferation (10, 11) and the expression of many genes, including c-fos (8, 12), Egr-1 (early growth response-1) (8, 13), and Cox-2 (cyclooxygenase-2) (8, 12), all of which have been shown to play a role in bone formation in vivo (14 -17).The signaling molecules that have been shown to regulate mechanically induced proliferation in osteoblasts include NO (10,[18][19][20], prostaglandin E 2 , prostacyclin (10, 18 -20), and ERK (10,11,18). Kapur et al. (11) demonstrated that ERK1...

show abstract

Phosphatidylinositol 3-Kinase p85α Subunit-Dependent Interaction with BCR/ABL-Related Fusion Tyrosine Kinases: Molecular Mechanisms and Biological Consequences

Cited by 25 publications

References 61 publications

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Oscillatory Flow-induced Proliferation of Osteoblast-like Cells Is Mediated by αvβ3 and β1 Integrins through Synergistic Interactions of Focal Adhesion Kinase and Shc with Phosphatidylinositol 3-Kinase and the Akt/mTOR/p70S6K Pathway

Contact Info

Product

Resources

About