Distinct roles of the mTOR components Rictor and Raptor in MO7e megakaryocytic cells

Fuhler, Gwenny M.; Tyl, M.R.; Olthof, Sandra; Drayer, A. Lyndsay; Blom, Nel R.; Vellenga, Edo

doi:10.1111/j.1600-0609.2009.01263.x

Cited by 33 publications

(28 citation statements)

References 47 publications

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“…While ribosomal S6 protein is considered a direct downstream target of PKB activity through mTOR-p70S6 signaling, we observed that although PKB phosphorylation is decreased upon inhibition of SHIP2, S6 phosphorylation is enhanced. However, mTOR signaling is complex, with positive and negative feedback loops via the mTORC1 and mTORC2 signaling complexes, and cellular levels of PKB and S6 phosphorylation are thus not always unidirectional [38]. Alternatively, SHIP2 may affect the mTOR pathway independently from PKB.…”

Section: Discussionmentioning

confidence: 99%

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

et al. 2016

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Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such “oncogenic” kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

et al. 2016

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“…43 In megakaryopoiesis, the mTOR/rictor complex affects megakaryopoiesis by regulating nuclear division and subsequent cell cycle progression, whereas raptor signaling protects cells from autophagic cell death. 44 Published work suggests that downregulation of rictor in C2C12 cells can inhibit mTORC2 signaling without inhibiting mTORC1; this prevented phosphorylation of Akt on Ser473 and stimulated protein synthesis. 12 Our data show that extensive depletion of raptor had no effect on p70S6K or rpS6 phosphorylation during myogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

mTOR kinase-dependent, but raptor-independent regulation of downstream signaling is important for cell cycle exit and myogenic differentiation

2014

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Myogenic differentiation in the C2C12 myoblast model system reflects a concerted and controlled activation of transcription and translation following the exit of cells from the cell cycle. Previously we have shown that the mTORC1 signaling inhibitor, RAD001, decreased protein synthesis rates, delayed C2C12 myoblast differentiation, decreased p70S6K activity but did not affect the hypermodification of 4E-BP1. Here we have further investigated the modification of 4E-BP1 during the early phase of differentiation as cells exit the cell cycle, using inhibitors to target mTOR kinase and siRNAs to ablate the expression of raptor and rictor. As predicted, inhibition of mTOR kinase activity prevented p70S6K, 4E-BP1 phosphorylation and was associated with an inhibition of myogenic differentiation. Surprisingly, extensive depletion of raptor did not affect p70S6K or 4E-BP1 phosphorylation, but promoted an increase in mTORC2 activity (as evidenced by increased Akt Ser473 phosphorylation). These data suggest that an mTOR kinase-dependent, but raptorindependent regulation of downstream signaling is important for myogenic differentiation.

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“…These findings may have important implications for approaches aimed at selectively reducing MC burden associated with inflammation, tumorigenesis, and MC proliferative disorders. Following on the reports of the roles of mTOR in cell growth and survival in other systems, [39][40][41][42][43] rapamycin has been investigated as a potential approach to block proliferating MCs. 44 However, this may in part be because of antisurvival effects through blockade of mTORC1.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells

Smrž

Kim

Zhang

et al. 2011

Blood

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Increased mast cell burden is observed in the inflamed tissues and affected organs and tissues of patients with mast cell proliferative disorders. However, normal mast cells participate in host defense, so approaches to preferentially target clonally expanding mast cells are needed. We found that mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) are up-regulated in neoplastic and developing immature mast cells compared with their terminally differentiated counterparts. Elevated mTOR mRNA was also observed in bone marrow mononuclear cells of patients exhibiting mast-cell hyperplasia. Selective inhibition of mTORC1 and mTORC2 through genetic and pharmacologic manipulation revealed that, whereas mTORC1 may contribute to mast-cell survival, mTORC2 was only critical for homeostasis of neoplastic and dividing immature mast cells. The cytostatic effect of mTORC2 down-regulation in proliferating mast cells was determined to be via inhibition of cell-cycle progression. Because mTORC2 was observed to play little role in the homeostasis of differentiated, nonproliferating, mature mast cells, these data provide a rationale for adopting a targeted approaching selectively inhibiting mTORC2 to effectively reduce the proliferation of mast cells associated with inflammation and disorders of mast cell proliferation while leaving normal differentiated mast cells largely unaffected. IntroductionMast cells (MCs) are considered to be critical components of both the innate and acquired immune defense systems. 1 Central to these functions is the ability of MCs to release a plethora of inflammatory mediators after activation through cell-surface receptors, primarily the high-affinity receptors for IgE (Fc⑀RI). 2 Although these reactions are considered to have evolved to protect host organisms against invading parasites and other microorganisms, 3 inappropriate or exaggerated activation of MCs manifests the reactions associated with allergic diseases.MCs develop from bone marrow (BM) CD13 ϩ /CD34 ϩ /CD117 (KIT) ϩ progenitor cells that enter into circulation and mature during migration to and residency in their target tissues. 4 MC numbers within tissues appear to be tightly regulated, with a several-fold increase in numbers occurring in inflammatory conditions and even higher numbers in association with parasitic inflammation. Clonal MC disorders may result in 10-fold or greater numbers of MCs in tissues such as the BM, liver, and spleen. [5][6] Similarly, a dysregulated increase in MC numbers is also observed in certain types of cancer, and in that context may contribute to cancer progression. [7][8][9] We observed previously that the mammalian target of rapamycin (mTOR) is overexpressed and constitutively phosphorylated in neoplastic MCs regardless of whether activating mutations in the MC growth factor receptor KIT are present. 10 MTOR is a serine/ threonine kinase that regulates divergent signaling pathways depending on its interactions with 2 regulatory proteins: raptor, a major component of mTOR complex 1 (mTORC1), a...

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Distinct roles of the mTOR components Rictor and Raptor in MO7e megakaryocytic cells

Cited by 33 publications

References 47 publications

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

mTOR kinase-dependent, but raptor-independent regulation of downstream signaling is important for cell cycle exit and myogenic differentiation

mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells

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