PLD regulates myoblast differentiation through the mTOR-IGF2 pathway

Yoon, Mee Sup; Chen, Jiawen

doi:10.1242/jcs.022566

Cited by 63 publications

(75 citation statements)

References 47 publications

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“…The reported plasma membrane localization of PLD2, 69,71 seems to disagree with such a role. Indeed, our knockdown studies in both HEK293 cells 35 and C2C12 myoblasts 72 suggest that PLD2 is dispensable for mTORC1 activation. However, the presence of PLD2 in the cytoplasm, albeit not a major fraction, cannot be ruled out.…”

Section: Pld1 or Pld2?mentioning

confidence: 90%

“…26 A PLD1-mTOR pathway is also found to be required for skeletal myoblast differentiation by regulating the expression of insulin-like growth factor II. 72 Furthermore, mTOR activation in Syk-dependent survival of follicular lymphoma cells, 82 lacritin regulation of restricted epithelial proliferation, 83 melanogenesis of mouse B16 melanoma cells, 84 and collagen type I production in human dermal fibroblasts 85 all involve PLD and PA.…”

Section: The Pld-mtor Connection: An Asset For Mammalsmentioning

confidence: 99%

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mTOR signaling: PLD takes center stage

Sun¹,

Chen

2008

Cell Cycle

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Section: Pld1 or Pld2?mentioning

confidence: 90%

Section: The Pld-mtor Connection: An Asset For Mammalsmentioning

confidence: 99%

mTOR signaling: PLD takes center stage

Sun¹,

Chen

2008

Cell Cycle

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“…Lentivirus packaging and testing were performed as previously described (24). The Sigma clone ID for the shRNA constructs used in this study are: mTOR #1, NM_020009.1-7569s1c1; mTOR #2, NM_020009.1-5493s1c1; rictor #1, NM_030168.2-6240s1c1, rictor #2, NM_030168.2-5030s1c1; Rheb #1, NM_053075 .2-740s1c1, Rheb #2, NM_053075.2-339s1c1; IRS1 #1, NM_010570.4 -2308s21c1, IRS1 #2, NM_010570.2-3585s1c1; S6K1 #1, NM_028259.1-264s1c1; S6K1 #2, NM_028259.1-616s1c1; raptor #1, NM_028898.1-3729s1c1.…”

Section: Methodsmentioning

confidence: 99%

Raptor and Rheb Negatively Regulate Skeletal Myogenesis through Suppression of Insulin Receptor Substrate 1 (IRS1)

Yoon

Chen

2011

Journal of Biological Chemistry

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The mammalian target of rapamycin (mTOR) is essential for skeletal myogenesis through controlling distinct cellular pathways. The importance of the canonical mTOR complex 1 signaling components, including raptor, S6K1, and Rheb, had been suggested in muscle maintenance, growth, and metabolism. However, the role of those components in myogenic differentiation is not entirely clear. In this study we have investigated the functions of raptor, S6K1, and Rheb in the differentiation of C2C12 mouse myoblasts. We find that although mTOR knockdown severely impairs myogenic differentiation as expected, the knockdown of raptor, as well as Rheb, enhances differentiation. Consistent with a negative role for these proteins in myogenesis, overexpression of raptor or Rheb inhibits C2C12 differentiation. On the other hand, neither knockdown nor overexpression of S6K1 has any effect. Moreover, the enhanced differentiation elicited by raptor or Rheb knockdown is accompanied by increased Akt activation, elevated IRS1 protein levels, and decreased Ser-307 (human Ser-312) phosphorylation on IRS1. Finally, IRS1 knockdown eliminated the enhancement in differentiation elicited by raptor or Rheb knockdown, suggesting that IRS1 is a critical mediator of the myogenic functions of raptor and Rheb. In conclusion, the Rheb-mTOR/raptor pathway negatively regulates myogenic differentiation by suppressing IRS1-PI3K-Akt signaling. These findings underscore the versatility of mTOR signaling in biological regulations and implicate the existence of novel mTOR complexes and/or signaling mechanism in skeletal myogenesis.During embryonic skeletal myogenesis, cells in somites commit to myogenic lineage and become myoblasts, which differentiate and fuse to form multinucleated myofibers (1). This is a highly coordinated process where various environmental cues and signaling pathways integrate to regulate the formation of skeletal muscle (2, 3). This process is largely recapitulated by the in vitro differentiation of myoblasts, such as the C2C12 mouse satellite cell line. Upon growth factor withdrawal, these cells produce insulin-like growth factor II (IGF-II), 2 which in an autocrine fashion stimulates myogenic differentiation (4). One of the critical pathways downstream of myogenic IGF signaling is the PI3K-Akt pathway (5, 6), and insulin receptor substrate 1 (IRS1) is a well-established mediator of IGF receptor activation of downstream signaling (7). mTOR, the mammalian target of rapamycin, has long been recognized as a nutrient-and energy-sensing signaling hub regulating a wide spectrum of cellular processes including proliferation, growth, survival, differentiation, and metabolism (8). It nucleates two distinct biochemical complexes: the raptor-associated mTORC1 is acutely sensitive to rapamycin, and it targets S6K1 and 4E-BP1 to regulate translation initiation, among other functions; the rictor-associated mTORC2 is a kinase for the multifunctional kinase Akt and it also regulates cytoskeleton reorganization (9). Although mTORC2 was initially characte...

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“…Clone IDs are: Flt3L #1, TRCN0000025059; Flt3L #2, TRCN0000025060; Flt3 #1, TRCN0000023739; Flt3 #2, TRCN0000378645; p120RasGAP, TRCN0000322311; Erk1, TRCN0000234920; Erk2, TRCN0000360489. Lentivirus packaging was performed as previously described (Yoon and Chen, 2008). Virally transduced C2C12 cells were selected in 3 mg/ml puromycin for 2 days, followed by differentiation for 3 days.…”

Section: Lentivirus-mediated Rnaimentioning

confidence: 99%

Flt3L is a novel regulator of skeletal myogenesis

Waldemer

Nalluri

et al. 2013

Journal of Cell Science

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SummaryVarious cues initiate multiple signaling pathways to regulate the highly coordinated process of skeletal myogenesis. Myoblast differentiation comprises a series of ordered events starting with cell cycle withdrawal and ending with myocyte fusion, with each step probably controlled by multiple extracellular signals and intracellular signaling pathways. Here we report the identification of Fms-like tyrokine kinase 3 ligand (Flt3L) signaling as a novel regulator of skeletal myogenesis. Flt3L is a multifunctional cytokine in immune cells, but its involvement in skeletal muscle formation has not been reported. We found that Flt3L is expressed in C2C12 myoblasts, with levels increasing throughout differentiation. Knockdown of Flt3L, or its receptor Flt3, suppresses myoblast differentiation, which is rescued by recombinant Flt3L or Flt3, respectively. Differentiation is not rescued, however, by recombinant ligand when the receptor is knocked down, or vice versa, suggesting that Flt3L and Flt3 function together. Flt3L knockdown also inhibits differentiation in mouse primary myoblasts. Both Flt3L and Flt3 are highly expressed in nascent myofibers during muscle regeneration in vivo, and Flt3L siRNA impairs muscle regeneration, validating the physiological significance of Flt3L function in myogenesis. We have identified a cellular mechanism for the myogenic function of Flt3L, as we show that Flt3L promotes cell cycle exit that is necessary for myogenic differentiation. Furthermore, we identify Erk as a relevant target of Flt3L signaling during myogenesis, and demonstrate that Flt3L suppresses Erk signaling through p120RasGAP. In summary, our work reveals an unexpected role for an immunoregulatory cytokine in skeletal myogenesis and a new myogenic pathway.

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PLD regulates myoblast differentiation through the mTOR-IGF2 pathway

Cited by 63 publications

References 47 publications

mTOR signaling: PLD takes center stage

mTOR signaling: PLD takes center stage

Raptor and Rheb Negatively Regulate Skeletal Myogenesis through Suppression of Insulin Receptor Substrate 1 (IRS1)

Flt3L is a novel regulator of skeletal myogenesis

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