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二十多年前Raf作为一种独特的癌基因被发现，此后人们对其进行了大量研究，并确立了其在Ras—Raf-MEK—ERK经典信号转导通路中的地位。Ras—Raf-MEK—ERK通路是参与调节细胞增生、分化和凋亡等生物学过程的一条重要的信号转导通路，其与肿瘤的发生关系密切。而Raf，作为这一信号转导通路中的关键分子，对于该通路的信号转导具有决定性作用。关于Ras在肺癌发生中的作用已经进行了大量深入的研究，近年来关于Raf激酶在肺癌发生及治疗中作用的研究也取得了一定进展，本文对此进行着重论述。

It is widely known that branched chain amino acids（BCAA） are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA（isoleucine, leucine and valine） regulate many key signaling pathways, the most classic of which is the activation of the m TOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including：（1） Insufficient or excessive levels of BCAA in the diet enhances lipolysis.（2） BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters.（3）Supplementation of leucine in the diet enhances meat quality in finishing pigs.（4） BCAA are beneficial for mammary health, milk quality and embryo growth.（5） BCAA enhance intestinal development, intestinal amino acid transportation and mucin production.（6） BCAA participate in up-regulating innate and adaptive immune responses.In addition, abnormally elevated BCAA levels in the blood（decreased BCAA catabolism） are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.

Dear Editor, Ethylene gas is a classic phytohormone regulating many aspects of plant development and defense. Molecu- lar and genetic studies have revealed a highly conserved signaling pathway starting from the ER membrane-as- sociated receptors to transcription factors in the nucleus [1]. EIN2 （ETHYLENE INSENSITIVE2） is an essential positive regulator of ethylene signaling in Arabidopsis thaliana, as loss-of-function ein2 mutants are completely insensitive to ethylene [2]. EIN2 encodes a 1 294 amino acid protein that comprises a membrane-spanning amino terminus and a functionally unknown carboxyl terminus [3]. E1N2 was reported to localize at the ER membrane when transiently expressed in tobacco leaf cells [4]. EIN3 （ETHYLENE INSENSITIVE3） and its homolog EIL 1 （EIN3-LIKE 1） are two nuclear-localized transcrip- tion factors genetically acting downstream of EIN2 [5, 6]. However, it remains a long mystery on how the ethyl- ene signal is transmitted from ER-located EIN2 into the nucleus to modulate EIN3/EILl-directed transcription. Here we report that the carboxyl end of E1N2 （CEND） is a trafficking signal translocating from ER membrane to the nucleus. Ethylene signal promotes the cleavage of CEND from ER-located E1N2, and facilitates its nuclear localization to stabilize E1N3 protein.

The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Latsl/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DcAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Latsl/2-binding site on the Merlin FERM domain is physically blocked by Merlin＇s auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin＇s binding to Latsl/2. Phosphorylation of Ser518 outside the Merlin＇s auto-inhibitory tail does not obviously alter Merlin＇s conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin- binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

Dear Editor, Plants establish beneficial symbiotic associations with arbuscular mycorrhizal fungi, which colonize the root cortex, building specialized structures called arbuscules that facilitate nutrient exchange. The association occurs following plant recognition of lipochitooligosaccharides （LCOs） from mycorrhizal fungi, which activates the symbiosis signaling pathway prior to mycorrhizal coloni- zation. Here we show that SLR1/DELLA,

SARS coronavirus （SARS-CoV） develops an antagonis- tic mechanism by which to evade the antiviral activities of interferon （IFN）. Previous studies suggested that SARS-CoV papain-like protease （PLpro） inhibits activa- tion of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism（s） used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro effi- ciently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain （PLpro-TM） from SARS-CoV inhibits STING/ TBKl/IKKE-mediated activation of type I IFNs and dis- rupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBKI. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKK~, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activa- tion of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is dis- rupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3- TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction withSTING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.

The defining features of embryonic stem cells （ESCs） are their self-renewing and pluripotent capacities. Indeed, the ability to give rise into all cell types within the organism not only allows ESCs to function as an ideal in vitro tool to study embryonic development, but also offers great therapeutic potential within the field of regenerative medicine. However, it is also this same remarkable developmental plasticity that makes the efficient control of ESC differentiation into the desired cell type very difficult. Therefore, in order to harness ESCs for clinical applications, a detailed understanding of the molecular and cellular mechanisms controlling ESC pluripotency and lineage commitment is necessary. In this respect, through a variety of transcriptomic approaches, ESC pluripotency has been found to be regulated by a system of ESC-associated transcription factors; and the external signalling environment also acts as a key factor in modulating the ESC transcriptome. Here in this review, we summarize our current understanding of the transcriptional regulatory network in ESCs, discuss how the control of various signalling pathways could influence pluripotency, and provide a future outlook of ESC research.

Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.

Definitive endoderm differentiation is crucial for generating respiratory and gastrointestinal organs including pancreas and liver. However, whether epigenetic regulation contributes to this process is unknown. Here, we show that the H3K27me3 demethylases KDM6A and KDM6B play an important role in endoderm differentiation from human ESCs. Knockdown of KDM6A or KDM6B impairs endoderm differentiation, which can be rescued by sequential treatment with WNT agonist and antagonist. KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive en- doderm differentiation, respectively. Our study not only uncovers an important role of the H3K27me3 demethylases in definitive endoderm differentiation, but also reveals that they achieve this through modulating the WNT signaling pathway.

The C-type lectin receptors （CLRs） belong to a large family of proteins that contain a carbohydrate recognition domain （CRD） and calcium binding sites on their extracellular domains. Recent studies indicate that many CLRs, such as Dectin-1, Dectin-2 and Mincle, function as pattern recognition receptors （PRRs） recognizing carbohydrate ligands from infected microorganisms. Upon ligand binding, these CLRs induce multiple signal transduction cascades through their own immunoreceptor tyrosine-based activation motifs （ITAMs） or interacting with ITAM-containing adaptor proteins such as FcRy. Emerging evidence indicate that CLR-induced signaling cascades lead to the activation of nuclear factor kappaB （NF-KB） family of transcriptional factors through a Syk- and CARD9-dependent pathway（s）. The activation of NF-κB plays a critical role in the induction of innate immune and inflammatory responses following microbial infection and tissue damages. In this review, we will summarize the recent progress on the signal transduction pathways induced by CLRs. and how these CLRs activate NF-κB and contribute to innate immune and inflammatory responses.