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Journal of Cell Science
Cambridge University Press
Journal of Cell Science

Cambridge University Press

0021-9533

Journal of Cell Science/Journal Journal of Cell ScienceSCIISTP
正式出版
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    PDGFR dimer-specific activation, trafficking and downstream signaling dynamics

    Madison A. RogersMaria B. CampanaRobert LongKatherine A. Fantauzzo...
    1页
    查看更多>>摘要：Signaling through the platelet-derived growth factor receptors (PDGFRs) plays a critical role in multiple cellular processes during development. The two PDGFRs, PDGFR alpha and PDGFRp, dimerize to form homodimers and/or heterodimers. Here, we overcome previous limitations in studying PDGFR dimer-specific dynamics by generating cell lines stably expressing C-terminal fusions of each PDGFR with bimolecular fluorescence complementation (BiFC) fragments corresponding to the N-terminal or C-terminal regions of the Venus fluorescent protein. We find that PDGFRp receptors homodimerize more quickly than PDGFRa receptors in response to PDGF ligand, with increased levels of autophosphorylation. Furthermore, we demonstrate that PDGFRa homodimers are trafficked and degraded more quickly, whereas PDGFRp homodimers are more likely to be recycled back to the cell membrane. We show that PDGFRp homodimer activation results in a greater amplitude of phospho-ERK1/2 and phospho-AKT signaling, as well as increased proliferation and migration. Finally, we demonstrate that inhibition of clathrin-mediated endocytosis leads to changes in cellular trafficking and downstream signaling, particularly for PDGFRa homodimers. Collectively, our findings provide significant insight into how biological specificity is introduced to generate unique responses downstream of PDGFR engagement.This article has an associated First Person interview with the first author of the paper.
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    The Great Resignation II

    1页
    查看更多>>摘要：Hey there! Gorgeous day, here. Warm, sunny, not too hot, and while I have a lot of work to do, I would much rather talk to you. ‘Tea’, anyone?If you are just joining us, we have been talking about the Great Resignation, especially as it applies to graduate students completing their degrees who have chosen not to continue on the rocky road to independent, academic research. By ‘academic’, I am not restricting myself to work done in universities; any research is academic if it is done in the spirit of self-motivated exploration - what we might call ‘independent research’. This could be done in universities, of course, but also in stand-alone institutes, hospitals or, if you are especially wealthy, in the basement of your castle (once upon a time, work in such a castle gave us the basics of oxidative phosphorylation and electron transport). Often, but not always, such academic research involves training the ‘next generation’ of scientists, and therein lies our dilemma. If many (or most) such trainees choose not to continue beyond a degree, a lot of academic science slows or maybe even stops.
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    Achieving sustainable transformation in science - green grassroots groups need nurturing from the top

    Dobbelaere JHeidelberger J.BBorgermann N
    1页
    查看更多>>摘要：Climate change is the greatest challenge of our time, and drastic climate action is needed urgently across industries and sectors to prevent the worst in terms of consequences. Although academic research brings great benefits to society, it leaves behind a considerable environmental footprint at the same time. This is particularly true for lab research within the life sciences. To reduce the climate impact of academic research, both bottom-up and top-down strategies are necessary. On the bottomup side, 'green' grassroots groups are emerging in academia, but most institutions fail to nurture and harness their potential for driving change. We report findings froma survey of 63 such grassroots groups operating in academic environments, highlighting that their main challenges in making research more sustainable include lack of time, budget, involvement in management decisions and support from management. For the first time, we map the inception, goals and structure of green grassroots groups in academia and outline concrete steps in overcoming barriers to harvest their full potential, thus making academic research fit for the future. ? 2022. Published by The Company of Biologists Ltd.
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    The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins

    Avais M. DaulatMonica S. WagnerStephane AudebertMalgorzata Kowalczewska...
    1页
    查看更多>>摘要：Upregulation of the developmental Wnt planar cell polarity (Wnt/PCP) pathway is observed in many cancers and is associated with cancer development. We have recently shown that PRICKLE1, a core Wnt/ PCP pathway component, is a marker of poor prognosis in triplenegative breast cancer (TNBC). PRICKLE1 is phosphorylated by the serine/threonine kinase MINK1 and contributes to TNBC cell motility and invasiveness. However, the identity of the substrates of MINK1 and the role of MINK1 enzymatic activity in this process remain to be addressed. We used a phosphoproteomic strategy to identify MINK1 substrates, including LL5p (also known as PHLDB2). LL5(3 anchors microtubules at the cell cortex through its association with CLASP proteins to trigger focal adhesion disassembly. LL5p is phosphorylated by MINK1, promoting its interaction with CLASP proteins. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in PRICKLE1-LL5p complex assembly and localization, as well as in cell migration. Analysis of gene expression data reveals that the concomitant upregulation of levels of mRNA encoding PRICKLE1 and LL5[3, which are MINK1 substrates, is associated with poor metastasis-free survival in TNBC patients. Taken together, our results suggest that MINK1 may represent a potential target for treatment of TNBC.
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    Proteasome granule formation is regulated through mitochondrial respiration and kinase signaling

    Kenrick A. WaiteJeroen Roelofs*
    1页
    查看更多>>摘要：In the yeast Saccharomyces cerevisiae, proteasomes are enriched in cell nuclei, in which they execute important cellular functions. Nutrient stress can change this localization, indicating that proteasomes respond to the metabolic state of the cell. However, the signals that connect these processes remain poorly understood. Carbon starvation triggers a reversible translocation of proteasomes to cytosolic condensates known as proteasome storage granules. Surprisingly, we observed strongly reduced levels of proteasome granules when cells had active cellular respiration prior to starvation. This suggests that the mitochondrial activity of cells is a determining factor in the response of proteasomes to carbon starvation. Consistent with this, upon inhibition of mitochondrial function, we observed that proteasomes relocalize to granules. These links between proteasomes and metabolism involve specific signaling pathways, as we identified a mitogen-activated protein kinase (MAPK) cascade that is critical to the formation of proteasome granules after respiratory growth but not following glycolytic growth. Furthermore, the yeast homolog of AMP kinase, Snf1, is important for proteasome granule formation induced by mitochondrial inhibitors, but it is dispensable for granule formation following carbon starvation. We propose a model in which mitochondrial activity promotes nuclear localization of the proteasome.This article has an associated First Person interview with the first author of the paper.
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    iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells

    Sieber BLu FStribbling S.MGrieve A.G...
    1页
    查看更多>>摘要：Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhom proteins, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here, we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 (also known as RHBDF2) to induce ADAM17- dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancerassociated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells. ? 2022. Published by The Company of Biologists Ltd.
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    Necroptosis at a glance

    Kidong KangChrista ParkFrancis Ka-Ming Chan
    1页
    查看更多>>摘要：Necroptosis, or programmed necrosis, is an inflammatory form of cell death with important functions in host defense against pathogens and tissue homeostasis. The four cytosolic receptor-interacting protein kinase homotypic interaction motif (RHIM)-containing adaptor proteins RIPK1, RIPK3, TRIP (also known as TICAM1) and ZBP1 mediate necroptosis induction in response to infection and cytokine or innate immune receptor activation. Activation of the RHIM adaptors leads to phosphorylation, oligomerization and membrane targeting of the necroptosis effector protein mixed lineage kinase domain-like (MLKL). Active MLKL induces lesions on the plasma membrane, leading to the release of pro-inflammatory damage-associated molecular patterns (DAMPs). Thus, activities of the RHIM adaptors and MLKL are tightly regulated by posttranslational modifications to prevent inadvertent release of immunogenic contents. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of the regulatory mechanisms of necroptosis and its biological functions in tissue homeostasis, pathogen infection and other inflammatory diseases.
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    Differential requirement for DICER1 activity during the development of mitral and tricuspid valves

    Shun YanYin PengJin LuSaima Shakil...
    1页
    查看更多>>摘要：Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. Here, we specifically inactivated Dicerl in the endocardium during cardiogenesis and found that Dicerl deletion caused congenital mitral valve stenosis and regurgitation, whereas it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of mi RNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. We thus reveal miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.
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    Cell scientist to watch - Fei Xavier Chen

    Fei Xavier Chen
    1页
    查看更多>>摘要：Fei Xavier Chen received his Bachelor’s degree from Shandong University, China, and his Master’s degree from Fudan University, where he worked on the structure and function of the histone demethylase LSD2. He then moved to the USA to join Ali Shilatifard’s group for his PhD, first at the Stowers Institute for Medical Research, Kansas City, and then at Northwestern University, Chicago. During this time he identified the transcription regulator PAF1 as a crucial player in the pausing-elongation step of transcription and its role in enhancer activation. He then did a short postdoc with Joan Massague at the Memorial Sloan Kettering Cancer Center, New York, to study transcriptional and epigenetic dysregulation in cancer progression. In 2019, Fei established his independent research group at the Fudan University in Shanghai; his lab uses a wide range of approaches to study the mechanisms of transcriptional regulation in health and disease, with a special focus on cancer.
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    First person - Vartika Sharma

    Vartika Sharma
    1页
    查看更多>>摘要：First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Vartika Sharma is first author on ‘Deltex modulates Dpp morphogen gradient formation and affects Dpp signaling in Drosophila’, published in JCS. Vartika conducted the research described in this article while a PhD student in Ashim Mukherjee’s lab at Banaras Hindu University, Varanasi, India. She is now a Postdoc in the lab of David Walker at University of California Los Angeles, USA, where she explores the molecular and cellular mechanisms of aging.
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    • Company Biologists Ltd