authoritative, comprehensive and systematic

Subcellular specialization of multifaceted 3'end modifying nucleotidyltransferases

The nucleus and gene expression: the center of the cyclone

Nuclear bodies: multifunctional companions of the genome

Bivalent histone modifications in early embryogenesis

Duel of the fates: the role of transcriptional circuits and noise in CD4+ cells

Quantitative analysis of gradient sensing: towards building predictive models of chemotaxis in cancer

Directed cell invasion and migration during metastasis

Cortical neurogenesis and morphogens: diversity of cues, sources and functions

Responding to chemical gradients: bacterial chemotaxis

Calcium gradients underlying cell migration

The JNK signal transduction pathway

The c-Jun NH2-terminal kinases (JNKs) are an evolutionarily conserved sub-group of mitogen-activated protein (MAP) kinases. Recent studies have improved our understanding of the physiological function of the JNK pathway. Roles of novel molecules that participate in the JNK pathway have been defined and new insight into the role of JNK in survival signaling, cell death, cancer and diabetes has been achieved. © 2006 Elsevier Ltd. All rights reserved.

Volume 19, Issue 2, 01 April 2007, Pp 142-149
Weston, C.R. | Davis, R.J.

DNA damage checkpoints: from initiation to recovery or adaptation

In response to diverse genotoxic stresses, cells activate DNA damage checkpoint pathways to protect genomic integrity and promote survival of the organism. Depending on DNA lesions and context, damaged cells with alarmed checkpoints can be eliminated by apoptosis or silenced by cellular senescence, or can survive and resume cell cycle progression upon checkpoint termination. Over the past two years a plethora of mechanistic studies have provided exciting insights into the biology and pathology…

Volume 19, Issue 2, 01 April 2007, Pp 238-245
Bartek, J. | Lukas, J.

Wnt/β-catenin signaling in cancer stemness and malignant behavior

Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/β-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling…

Volume 19, Issue 2, 01 April 2007, Pp 150-158
Fodde, R. | Brabletz, T.

Wnt/β-catenin signaling: new (and old) players and new insights

Wnt/β-catenin signaling has central roles in embryogenesis and human diseases including cancer. A central scheme of the Wnt pathway is to stabilize the transcription coactivator β-catenin by preventing its phosphorylation-dependent degradation. Significant progress has been made toward the understanding of this crucial regulatory pathway, including the protein complex that promotes β-catenin phosphorylation-degradation, and the mechanism by which the extracellular Wnt ligand engages cell…

Volume 20, Issue 2, 01 April 2008, Pp 119-125
Huang, H. | He, X.

Tubulin modifications and their cellular functions

All microtubules are built from a basic α/β-tubulin building block, yet subpopulations of microtubules can be differentially marked by a number of post-translational modifications. These modifications, conserved throughout evolution, are thought to act individually or in combination to control specific microtubule-based functions, analogous to how histone modifications regulate chromatin functions. Here we review recent studies demonstrating that tubulin modifications influence…

Volume 20, Issue 1, 01 February 2008, Pp 71-76
Hammond, J.W. | Cai, D. | Verhey, K.J.

Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

Chromosomal surfaces are ornamented with a variety of post-translational modifications of histones, which are required for the regulation of many of the DNA-templated processes. Such histone modifications include acetylation, sumoylation, phosphorylation, ubiquitination, and methylation. Histone modifications can either function by disrupting chromosomal contacts or by regulating non-histone protein interactions with chromatin. In this review, recent findings will be discussed regarding the…

Volume 20, Issue 3, 01 June 2008, Pp 341-348
Shilatifard, A.

Mechanisms regulating imprinted genes in clusters

Clustered imprinted genes are regulated by differentially methylated imprinting control regions (ICRs) that affect gene activity and repression in cis over a large region. Although a primary imprint signal for each of these clusters is DNA methylation, different mechanisms are used to establish and maintain these marks. The majority of ICRs are methylated in the maternal germline and are usually promoters for antisense transcripts whose elongation is associated with imprinting control in the…

Volume 19, Issue 3, 01 June 2007, Pp 281-289
Edwards, C.A. | Ferguson-Smith, A.C.

VEGFs and receptors involved in angiogenesis versus lymphangiogenesis

Vascular endothelial growth factors and their endothelial tyrosine kinase receptors are central regulators of vasculogenesis, angiogenesis and lymphangiogenesis. VEGF signalling through VEGFR-2 is the major angiogenic pathway, and blockage of VEGF/VEGFR-2 signalling is the first anti-angiogenic strategy for cancer therapy. VEGFR-1 seems to act as a negative regulator of VEGF-mediated angiogenesis during development, and as a stimulator of pathological angiogenesis when activated by its specific…

Volume 21, Issue 2, 01 April 2009, Pp 154-165
Lohela, M. | Bry, M. | Tammela, T. | Alitalo, K.

Exosomes - vesicular carriers for intercellular communication

Cells release different types of vesicular carriers of membrane and cytosolic components into the extracellular space. These vesicles are generated within the endosomal system or at the plasma membrane. Among the various kinds of secreted membrane vesicles, exosomes are vesicles with a diameter of 40-100 nm that are secreted upon fusion of multivesicular endosomes with the cell surface. Exosomes transfer not only membrane components but also nucleic acid between different cells, emphasizing…

Volume 21, Issue 4, 01 August 2009, Pp 575-581
Simons, M. | Raposo, G.

Mammalian autophagy: Core molecular machinery and signaling regulation

Autophagy, a cellular catabolic pathway, is evolutionarily conserved from yeast to mammals. Central to this process is the formation of autophagosomes, double-membrane vesicles responsible for delivering long-lived proteins and excess or damaged organelle into the lysosome for degradation and reuse of the resulting macromolecules. In addition to the hallmark discovery of core molecular machinery components involved in autophagosome formation, complex signaling cascades controlling autophagy…

Volume 22, Issue 2, 01 April 2010, Pp 124-131
Yang, Z. | Klionsky, D.J.

RNA-mediated chromatin-based silencing in plants

Plants have evolved an elaborate transcriptional machinery dedicated to eliciting sequence-specific, chromatin-based gene silencing. Two Pol II-related, plant-specific RNA polymerases, named Pol IV and Pol V, collaborate with proteins of the RNA interference machinery to generate long and short noncoding RNAs involved in epigenetic regulation. As revealed by a variety of genetic, molecular, and genomic technologies, these RNAs are used extensively in plants to direct the establishment, spread,…

Volume 21, Issue 3, 01 June 2009, Pp 367-376
Matzke, M. | Kanno, T. | Daxinger, L. | Huettel, B. | Matzke, A.J.

Assembly and biological role of podosomes and invadopodia

Regulated tissue invasion via motile and lytic events is critical for physiological processes such as immune system function and inflammatory responses, wound healing, and organ development, but pathological subversion of this process drives tumour cell invasion and metastasis. Cell migration and invasion require the integration of several processes that include: first, the local modulation of cytoskeleton structure and contractile forces; second, the turnover of substrate adhesions and their…

Volume 20, Issue 2, 01 April 2008, Pp 235-241
Gimona, M. | Buccione, R. | Courtneidge, S.A. | Linder, S.

ErbB receptors and signaling pathways in cancer

The ErbB receptor tyrosine kinases play important roles in normal physiology and in cancer. Epidermal growth factor receptor (EGFR) and ErbB2 in particular are mutated in many epithelial tumors, and clinical studies suggest that they play roles in cancer development and progression. These receptors have been intensely studied, not only to understand the mechanisms underlying their oncogenic potential, but also to exploit them as therapeutic targets. ErbB receptors activate a multiplicity of…

Volume 21, Issue 2, 01 April 2009, Pp 177-184
Hynes, N.E. | MacDonald, G.

Negative regulation of TGF-β receptor/Smad signal transduction

Members of the transforming growth factor-β (TGF-β) family are highly conserved multifunctional cell-cell signaling proteins that are of key importance for controlling embryogenesis and tissue homeostasis. At first glance, signaling through TGF-β family members appears to be a simple process: ligands bind to specific serine/threonine kinase transmembrane receptors, which activate intracellular Smad effector proteins, which in turn relay the signal to the nucleus to control gene transcription.…

Volume 19, Issue 2, 01 April 2007, Pp 176-184
Itoh, S. | ten Dijke, P.

Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells

MicroRNAs (miRNAs) are 20-nt-long to 24-nt-long noncoding RNAs acting as post-transcriptional regulators of gene expression in animals and plants. In mammals, more than 50% of mRNAs are predicted to be the subject of miRNA-mediated control but mechanistic aspects of the regulation are not fully understood and different studies have produced often-contradictory results. miRNAs can affect both the translation and stability of mRNAs. In this report, we review current progress in understanding how…

Volume 21, Issue 3, 01 June 2009, Pp 452-460
Chekulaeva, M. | Filipowicz, W.

The EGF receptor family: spearheading a merger of signaling and therapeutics

The ErbB receptor tyrosine kinases evolved as key regulatory entities enabling the extracellular milieu to communicate with the intracellular machinery to bring forth the appropriate biological response in an ever-changing environment. Since its discovery, many aspects of the ErbB family have been deciphered, with emphasis on aberration of signaling in human diseases. However, only now, with the availability of the atomic coordinates of these receptors, can we construct a comprehensive model of…

Volume 19, Issue 2, 01 April 2007, Pp 124-134
Bublil, E.M. | Yarden, Y.

Structure and mechanics of integrin-based cell adhesion

Integrins are α/β heterodimeric adhesion glycoprotein receptors that regulate a wide variety of dynamic cellular processes such as cell migration, phagocytosis, and growth and development. X-ray crystallography of the integrin ectodomain revealed its modular architecture and defined its metal-dependent interaction with extracellular ligands. This interaction is regulated from inside the cell (inside-out activation), through the short cytoplasmic α and β integrin tails, which also mediate…

Volume 19, Issue 5, 01 October 2007, Pp 495-507
Arnaout, M.A. | Goodman, S.L. | Xiong, J.-P.

ESCRT complexes and the biogenesis of multivesicular bodies

Multivesicular bodies (MVBs) are crucial intermediates in the trafficking of ubiquitinated receptors and other cargo destined for lysosomes. The formation of MVBs by invagination of the endosomal limiting membrane is catalyzed by the endosomal sorting complex required for transport (ESCRT) complexes, a process that has recently been visualized in three-dimensional detail by electron tomography. Structural and biochemical analysis of the upstream components, Vps27-Hse1, ESCRT-I, and ESCRT-II,…

Volume 20, Issue 1, 01 February 2008, Pp 4-11
Hurley, J.H.

Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation

The regulation of gene expression requires a wide array of protein factors that can modulate chromatin structure, act at enhancers, function as transcriptional coregulators, or regulate insulator function. Poly(ADP-ribose) polymerase-1 (PARP-1), an abundant and ubiquitous nuclear enzyme that catalyzes the NAD+-dependent addition of ADP-ribose polymers on a variety of nuclear proteins, has been implicated in all of these functions. Recent biochemical, genomic, proteomic, and cell-based studies…

Volume 20, Issue 3, 01 June 2008, Pp 294-302
Kraus, W.L.

FoxO transcription factors in the maintenance of cellular homeostasis during aging

The FoxO family of Forkhead transcription factors functions at the interface of tumor suppression, energy metabolism, and organismal longevity. FoxO factors are key downstream targets of insulin, growth factor, nutrient, and oxidative stress stimuli that coordinate a wide range of cellular outputs. FoxO-dependent cellular responses include gluconeogenesis, neuropeptide secretion, atrophy, autophagy, apoptosis, cell cycle arrest, and stress resistance. This review will discuss the roles of the…

Volume 20, Issue 2, 01 April 2008, Pp 126-136
Salih, D.A. | Brunet, A.

Retromer

The retromer is a heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network. The mammalian retromer complex comprises a sorting nexin dimer composed of a still undefined combination of SNX1, SNX2, SNX5 and SNX6, and a cargo-recognition trimer composed of Vps26, Vps29 and Vps35. The SNX subunits contain PX and BAR domains that allow binding to PI(3)P enriched, highly curved…

Volume 20, Issue 4, 01 August 2008, Pp 427-436
Bonifacino, J.S. | Hurley, J.H.

Stem cell regulation by polycomb repressors: postponing commitment

Polycomb group proteins (PcGs) are involved in gene repression through chromatin modifications and required for the maintenance of both embryonic and adult stem cells. Genome-wide studies demonstrate that genes targeted by PcG are predominantly developmental transcription factors. In embryonic stem cells, these genes carry not only a repressive PcG mark but also an activating mark, resulting in so-called 'bivalent domains'. New data suggest that genes with bivalent domains are primed for…

Volume 20, Issue 2, 01 April 2008, Pp 201-207
Pietersen, A.M. | van Lohuizen, M.

Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition

Members of the transforming growth factor-β (TGF-β) family have important roles during embryogenesis, as well as in the control of tissue homeostasis in the adult. They exert their cellular effects via binding to serine/threonine kinase receptors. Members of the Smad family of transcription factors are important intracellular messengers, and recent studies have shown that the ubiquitin ligase TRAF6 mediates other specific signals. TGF-β signaling is tightly controlled by post-translational…

Volume 21, Issue 2, 01 April 2009, Pp 166-176
Heldin, C.-H. | Landström, M. | Moustakas, A.

Polycomb complexes and epigenetic states

Important advances in the study of Polycomb Group (PcG) complexes in the past two years have focused on the role of this repressive system in programing the genome. Genome-wide analyses have shown that PcG mechanisms control a large number of genes regulating many cellular functions and all developmental pathways. Current evidence shows that, contrary to the classical picture of their role, PcG complexes do not set a repressed chromatin state that is maintained throughout development but have a…

Volume 20, Issue 3, 01 June 2008, Pp 266-273
Schwartz, Y.B. | Pirrotta, V.

Signaling on the endocytic pathway

Endocytosis regulates many cellular signaling processes by controlling the number of functional receptors available at the cell surface. Conversely, some signaling processes regulate the endocytic pathway. Furthermore, various cellular signaling events appear to occur on endosome membranes. The endocytic pathway, by providing a set of dynamic and biochemically specialized endomembrane structures that physically communicate with the plasma membrane, is increasingly viewed as a highly flexible…

Volume 19, Issue 4, 01 August 2007, Pp 436-445
von Zastrow, M. | Sorkin, A.

Necroptosis as an alternative form of programmed cell death

Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transition

Directed cell invasion and migration during metastasis

Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation

Polycomb: a paradigm for genome organization from one to three dimensions

TOR in the immune system

Epithelial polarity and morphogenesis

Deconstructing the centriole: structure and number control

Making sense of transcribing chromatin

mTOR signaling in disease