Reviews & Analysis

The basic elements of the transforming growth factor-β (TGFβ) pathway came to light more than a decade ago. Since then, the multifunctional nature and medical relevance of this pathway have relentlessly been elucidated. The old mystery of how the context determines the cellular response to TGFβ and its many malfunctions is only starting to be unravelled.

The characterization of dynamic contacts that form between the endoplasmic reticulum and mitochondria have highlighted the different ways in which the functions of these organelles can be coordinated. These structures may also allow co-regulation of distinct processes.

Research on the cadherin–junctional actin interaction has focused on how the two physically interact. However, the actin cytoskeleton is dynamic, regulated by a network of proteins, so a broader perspective that takes this into account may provide new insights on cadherin cell–cell contacts and on the role of cadherins in disease.

STIM proteins sense subtle changes in the levels of endoplasmice reticulum (ER)-stored Ca²⁺ and respond by regulating extracellular Ca²⁺entry and cell signalling. New structural and functional data have shed light on the role of STIM proteins as stress sensors.

Like all cell types, stem cells are subject to DNA damage, which results in the activation of checkpoint proteins, for example p53. These checkpoint responses lead to the clearance of damaged cells by cell-intrinsic and cell-extrinsic mechanisms, preventing carcinogenesis, but may also impair stem cell and tissue maintenance, thereby promoting ageing.

The super elongation complex (SEC) consists of the RNA polymerase II (Pol II) elongation factors eleven-nineteen Lys-rich leukaemia (ELL) proteins, positive transcription elongation factor b (P-TEFb) and several frequent mixed lineage leukaemia (MLL) translocation partners. The SEC controls transcription elongation in the presence or absence of promoter-proximal paused Pol II, and its gene target specificity depends on protein components forming distinct SEC complexes.

Forces transmitted through cell–cell and cell–extracellular matrix adhesions control cell fate decisions. But how are mechanical cues translated into gene expression programmes? The transcriptional regulators YAP and TAZ have arisen as convergence points of mechanical and biochemical signals.

Ca²⁺ uptake through specialized transporters allows mitochondria to act as buffers of intracellular Ca²⁺ levels. Moreover, mitochondrial Ca²⁺ signalling regulates vital processes, including metabolism and cell death. Therefore, mitochondrial Ca²⁺signalling remains at the epicentre of cell biological research.

Ubiquitin can form eight structurally distinct chain types. Recent advances have elucidated the mechanisms of linkage-specific chain assembly, recognition and hydrolysis. The cellular roles of the six 'atypical' ubiquitin chains (linked via Lys6, Lys11, Lys27, Lys29, Lys33 or Met1 of ubiquitin) are beginning to emerge, highlighting how they can each act as independent post-translational modifications.

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Studies using high-throughput genomic tools suggest that there is extensive crosstalk among epigenetic pathways that function at the level of DNA, histone and nucleosome. Mapping of higher-order chromatin structures and chromatin–nuclear matrix interactions provides insights into the three-dimensional organization of the genome and can reveal new rules of gene regulation.

Successful abscission — the final stage of cell division — involves the precise coordination of different events, culminating in the separation of two daughter cells. Endocytic and secretory vesicle trafficking, ESCRT-mediated scission and signalling through mitotic kinases have emerged as key players in this process.

The conservation and prevalence of inactive homologues in most enzyme families suggests that they may have significant functions that have been largely overlooked. Mechanistic understanding and evolutionary lessons are now emerging from the study of a broad range of such 'dead' enzymes including the recently discovered iRhoms.

The identification of an hydrogen sulfide (H₂S)-mediated post-translational modification (protein sulfhydration) has provided novel insights into H₂S signalling, which controls many cellular functions. As a result, a new research area has arisen that investigates how metabolic stress and other environmental signals influence protein function through Cys modification by H₂S.

Chromatin compaction has profound implications for the regulation of transcription, replication and DNA repair. Changes in nucleosome structure and stability — due to the incorporation of variant histones and post-translational modifications of histones — affect chromatin compaction. Chromatin structures are not nearly as uniform as previously assumed, which should be taken into account in the context of specific biological functions.

Membrane trafficking relies on changes in membrane identity, which are determined by RAB GTPases and phosphoinositides. Coordinated regulation of RABs and phosphoinositides, which is achieved by direct physical and functional interactions between their regulatory enzymes, is emerging as a central mechanism to ensure membrane trafficking fidelity.

Approximately half of human proteins are glycosylated, and the resulting diverse glycan patterns encode an additional level of information. The process of protein glycosylation is mediated by numerous enzymes with dynamic localization, regulation and specificity. High-throughput techniques facilitate the study of complex protein glycans and may give further insights into their roles in protein homeostasis, cell signalling and cell adhesion.

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein modification, the control of which is important for diverse cell biological processes and normal physiology. Common mechanistic themes are being characterized by which PARylation alters the functions of target proteins, and the PAR-binding modules that mediate this.

The centriole is crucial for the formation of flagella, cilia and centrosomes. The ultrastructure of the centriole reveals a striking ninefold radial arrangement of microtubules. Emerging insights into the molecular mechanisms of centriole assembly include the function of spindle assembly abnormal 6 (SAS-6) proteins in imparting the ninefold symmetry.

Six scientists in the field of stem cell research comment on our basic understanding of stem cells and other pluripotent cells, on their potential therapeutic use and on key challenges that remain.

The glucose transporter GLUT4 ensures controlled glucose uptake into fat and muscle cells. By targeting several steps in the membrane trafficking of GLUT4, insulin signalling allows tight regulation of glucose homeostasis and prevents the development of insulin resistance.