2014 Vol. 5(3)

Perspective
Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity
Pengda Liu, Jianping Guo, Wenjian Gan, Wenyi Wei
2014, 5(3): 171-177. doi: 10.1007/s13238-014-0021-8
Abstract:
Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers.
Letters
Structure basis for the unique specificity of medaka enteropeptidase light chain
Jin Xu, Shi Hu, Xiaoze Wang, Ziye Zhao, Xinyue Zhang, Hao Wang, Dapeng Zhang, Yajun Guo
2014, 5(3): 178-181. doi: 10.1007/s13238-013-0008-x
Abstract:
The gain of hydrogen peroxide resistance benefits growth fitness in mycobacteria under stress
Xiaojing Li, Jun Tao, Jiao Han, Xinling Hu, Yuling Chen, Haiteng Deng, Guangchun Zhang, Xiaoxiang Hu, Kaixia Mi
2014, 5(3): 182-185. doi: 10.1007/s13238-014-0024-5
Abstract:
Reviews
New insights into the regulation of Axin function in canonical Wnt signaling pathway
Xiaomin Song, Sheng Wang, Lin Li
2014, 5(3): 186-193. doi: 10.1007/s13238-014-0019-2
Abstract:
The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling:on one hand, Axin scaffolds the "β-catenin destruction complex" to promote β-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the "on" or "off" Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as posttranscriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling.
Telomere regulation in pluripotent stem cells
Yan Huang, Puping Liang, Dan Liu, Junjiu Huang, Zhou Songyang
2014, 5(3): 194-202. doi: 10.1007/s13238-014-0028-1
Abstract:
Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review, we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.
Inputs and outputs of insulin receptor
Yipeng Du, Taotao Wei
2014, 5(3): 203-213. doi: 10.1007/s13238-014-0030-7
Abstract:
The insulin receptor (IR) is an important hub in insulin signaling and its activation is tightly regulated. Upon insulin stimulation, IR is activated through autophosphorylation, and consequently phosphorylates several insulin receptor substrate (IRS) proteins, including IRS1-6, Shc and Gab1. Certain adipokines have also been found to activate IR. On the contrary, PTP, Grb and SOCS proteins, which are responsible for the negative regulation of IR, are characterized as IR inhibitors. Additionally, many other proteins have been identified as IR substrates and participate in the insulin signaling pathway. To provide a more comprehensive understanding of the signals mediated through IR, we reviewed the upstream and downstream signal molecules of IR, summarized the positive and negative modulators of IR, and discussed the IR substrates and interacting adaptor proteins. We propose that the molecular events associated with IR should be integrated to obtain a better understanding of the insulin signaling pathway and diabetes.
Research articles
p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells
Xiao-Xi Guo, Yang Li, Chao Sun, Dan Jiang, Ying-Jia Lin, Feng-Xie Jin, Seung-Ki Lee, Ying-Hua Jin
2014, 5(3): 224-234. doi: 10.1007/s13238-014-0027-2
Abstract:
We have recently reported that Ginsenoside Rh2 (GRh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-nonmutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for antitumor drug development.
Accelerated regeneration of the skeletal muscle in RNF13-knockout mice is mediated by macrophage-secreted IL-4/IL-6
Jiao Meng, Xiaoting Zou, Rimao Wu, Ran Zhong, Dahai Zhu, Yong Zhang
2014, 5(3): 235-247. doi: 10.1007/s13238-014-0025-4
Abstract:
RING finger protein 13 (RNF13) is a newly identified E3 ligase reported to be functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. In this study, the function of RNF13 in cardiotoxin-induced skeletal muscle regeneration was investigated using RNF13-knockout mice. RNF13-/- mice exhibited enhanced muscle regeneration -characterized by accelerated satellite cell proliferation -compared with wild-type mice. The expression of RNF13 was remarkably induced in macrophages rather than in the satellite cells of wild-type mice at the very early stage of muscle damage. This result indicated that inflammatory cells are important in RNF13-mediated satellite cell functions. The cytokine levels in skeletal muscles were further analyzed and showed that RNF13-/- mice produced greater amounts of various cytokines than wild-type mice. Among these, IL-4 and IL-6 levels significantly increased in RNF13-/- mice. The accelerated muscle regeneration phenotype was abrogated by inhibiting IL-4/IL-6 action in RNF13-/- mice with blocking antibodies. These results indicate that RNF13 deficiency promotes skeletal muscle regeneration via the effects on satellite cell niche mediated by IL-4 and IL-6.

Current Issue

May, 2019

Volume 10, Issue 5

Pages 313-387

About the cover

Left image:a mouse E9.5 embryo with Dgcr8 microRNA microprocessor conditionally knocked out in the heart. The heart in green was extremely dilated. Top right:cTnT immunostaining (in green) showed that the heart had very thin wall. Middle right:cTnT immunostaining (in red) showed lack of sarcomere structure in a microRNA free cardiomyocyte (CM). Insert:slow calcium transient frequency. Bottom right: transfection of miR-541 rescued sarcomere structure in Dgcr8 cKO CMs. cTnT immunostaining (in red) showed typical sarcomere structure. Insert:fast calcium transient frequency.

Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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