Volume 20 Issue 9, September 2018

Maintaining plasma membrane tension is important for eukaryotic cells. How altered membrane tension is sensed and relayed to downstream factors, such as the target of rapamyin complex 2 (TORC2), is poorly understood. Reorganization of a signalling lipid into discrete membrane domains is now shown to inactivate TORC2 in yeast.

Rag GTPases facilitate mTORC1 activation by recruiting it to Rheb at the lysosome when amino acids are abundant. A study now shows that the amino acid-induced change in the GTP/GDP-binding state of the Rag heterodimer paradoxically increases its dynamic release from the Ragulator at the lysosome and may limit mTORC1 activation.

During embryo development, concentration gradients of signalling molecules instruct formation of different cell types. How these gradients adapt to variable embryo sizes to form a properly scaled individual remains elusive. A simple system of an activator and an inhibitor, with different diffusion properties, may give an answer.

Asifa Akhtar is Director at the Max Planck Institute of Immunobiology and Epigenetics. Her lab focuses on chromatin and epigenetic regulation. A member of the European Molecular Biology Organisation, she received the European Life Science Organization award in 2008 and the Wilhelm Feldberg Prize in 2017.

Sandrine Etienne-Manneville investigates the molecular mechanisms underlying cell migration in health and disease. She is Head of the Cell Polarity, Migration and Cancer laboratory, Director of the CNRS UMR3691 unit at the Institut Pasteur, Paris, France, a professor of cell biology and a mother of four.

Maho Hamasaki is an associate professor at Osaka University, Japan. Maho’s laboratory focuses on investigating the mechanistic underpinnings of autophagy and the role of the autophagic process in disease.

Nancy Y. Ip is Vice President for Research and Graduate Studies, the Morningside Professor of Life Science, and Director of the State Key Laboratory of Molecular Neuroscience at the Hong Kong University of Science and Technology, Hong Kong, China. Her career in the field of neuroscience spans over three decades.

Professor Kum Kum Khanna heads the Signal Transduction Laboratory at the QIMR Berghofer Medical Research Institute in Brisbane, Australia. She studies the role of the DNA damage response in tissue homeostasis and disease, including how to exploit its dysregulation in breast cancer to develop targeted therapeutic approaches.

Melissa Little is an NHMRC Senior Principal Research Fellow and Cell Biology Theme Director at the Murdoch Children’s Research Institute in Melbourne, Australia. She also leads Stem Cells Australia, University of Melbourne. She studies kidney morphogenesis and regeneration using pluripotent stem cells.

Serena is a Cancer Research UK Advanced Clinician Scientist at the University of Cambridge. She studies mutation patterns in human DNA and finds ways to make it applicable in a clinical setting. Serena is a mother of two, loves music and being outdoors, and fights the forties with kung fu.

Melina Schuh did her PhD at the European Molecular Biology Laboratory with Jan Ellenberg. She became group leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, in 2009, and was appointed Director at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, in 2016.

M. Celeste Simon is Scientific Director of the Abramson Family Cancer Research Institute and Arthur H. Rubenstein, MBBCh Professor of Cell and Developmental Biology at the University of Pennsylvania. She studies tumour and stromal cell responses to variable oxygen and nutrient levels and is a devoted mentor of biomedical trainees.

Anne Simonsen is a Professor at the Department of Molecular Medicine at the Institute of Basic Medical Sciences of the University of Oslo, Norway. Her work focuses on lipid-binding proteins in membrane trafficking and autophagy, and their links to disease.

Shubha Tole obtained her BSc in Life Sciences and Biochemistry from St. Xavier’s College, Mumbai, India, in 1987. After a PhD from the California Institute of Technology in 1994, she did her postdoc at the University of Chicago. In 1999, she joined the Tata Institute of Fundamental Research, in Mumbai, as a faculty member.

Fiona Watt runs the Centre for Stem Cells and Regenerative Medicine at King’s College London and is an outspoken advocate for women scientists. Since April 2018, she has been on secondment as Executive Chair of the Medical Research Council, one of the major funders of biomedical research in the UK.

Mayana Zatz is Professor of Genetics and Director of the Human Genome and Stem-Cell Research Center at the University of São Paulo, Brazil. She works on neuromuscular disorders, ageing and, more recently, Zika virus and cancer. She has a prolific publication record and is actively involved in ethical aspects of genetic research.

In this Review, Tavernarakis and colleagues describe recent advances in delineating the molecular mechanisms that mediate mitophagy, and discuss the complex roles of this pathway in physiological and pathological contexts.

Chan Wah Hak et al. show how plasma membrane patches are primed for fast endophilin-mediated endocytosis and disassembly, in the absence of receptor stimulation, through FBP17 and CIP4 binding to SHIP2 and lamellipodin.

Almuedo-Castillo et al. show that extirpated embryos are reduced in size but exhibit normal proportions. Following a computational screen, the authors identify an increased concentration of the Nodal inhibitor Lefty to be responsible for the size scaling.

Using a small-molecule modulator of TORC2 signalling and a mechanosensitive probe, Riggi et al. reveal that decreased plasma membrane tension induces distinct PIP2-enriched domains that sequester and inactivate TORC2.

Lawrence et al. show that mTORC1 capture and activation at the lysosome are regulated by nutrients that destabilize Rag GTPase–Ragulator binding, and delineate how cancer-specific Rag mutants increase mTORC1 signalling.

Nichols et al. identify an SHP2 inhibitor that disrupts SOS1-mediated RAS–GTP loading with demonstrated efficacy in various types of tumour driven by mutant BRAF, NF1 or RAS.

Liu et al. show that reduced m⁶A mRNA methylation in endometrial cancer is oncogenic. Mechanistically, the AKT pathway is activated in these tumours due to altered expression of AKT regulators carrying m⁶A on their transcripts.

Castaño et al. show that primary breast tumours drive an IL-1β -mediated inflammatory response that inhibits cellular plasticity and metastatic colonization of metastasis-initiating cells.