Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase

Ahmed, Naheed N; Grimes, H. Leighton; Bellacosa, Alfonso; Chan, Tung O.; Tsichlis, Philip N.

doi:10.1073/pnas.94.8.3627

Cited by 487 publications

(378 citation statements)

References 28 publications

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“…Hyperactivation of mTORC1 in certain cell types results in suppression of AKT kinase activity through negative feedback, which is reflected by the hypophosphorylation of Thr308 and Ser493 (Harrington et al , 2004; Manning, 2004; Rozengurt et al , 2014). Since AKT has a known anti‐apoptotic activity (Ahmed et al , 1997; Dudek et al , 1997; Kauffmann‐Zeh et al , 1997; Kennedy et al , 1997), a potential inhibition of AKT could be involved in the observed cell death. However, in a panel of BL cell lines, TSC1 knockdown either resulted in an increase in Ser493 phosphorylation or did not change Ser493 phosphorylation of AKT, while we were unable to detect any Thr308 phosphorylation in our assay (Fig EV4A).…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

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Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

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“…Jak1 has been shown to be important for recruiting PI 3-K (Migone et al, 1998). Activated PI 3-K is most likely then responsible for activation of its downstream kinase Akt (protein kinase B) and p70 S6 kinase (Ahmed et al, 1997;Kuo et al, 1992), which are involved in antiapoptotic and proliferative activities in response to IL-2 (Reif et al, 1997). In addition, the protein tyrosine (Hatakeyama et al, 1991;Minami et al, 1993Minami et al, , 1995Miyazaki et al, 1998;Figure 2).…”

Section: How Does Il-2 Transduce Its Signals?mentioning

confidence: 99%

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

2000

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“…The PI3K-PKB/AKT pathway also plays a role in the anti-apoptosis function of IL-3. Overexpression of PKB/AKT, which leads to increased expression of c-myc, Bcl-2 and the Bcl-2 family member BAD, protects 32Dcl3 and BaF3 cells from IL-3 withdrawal-mediated apoptosis whereas expression of non-functional PKB/AKT acclerates apoptosis due to IL-3 withdrawal (Songyang et al, 1997;del Peso et al, 1997;Ahmed et al, 1997;Datta et al, 1997).…”

Section: Anti-apoptotic Pathwaysmentioning

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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Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase

Abstract: The interleukin-2 (IL-2) receptor (IL-2R) is composed of three subunits. Of these, IL-2R␣ is required for high-affinity IL-2 binding, while IL

Cited by 487 publications

References 28 publications

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

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

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