In S. cerevisiae, histone variant H2A.Z is deposited in euchromatin at the flanks of silent heterochromatin to prevent its ectopic spread. We show that H2A.Z nucleosomes are found at promoter regions of nearly all genes in euchromatin. They generally occur as two positioned nucleosomes that flank a nucleosome-free region (NFR) that contains the transcription start site. Astonishingly, enrichment at 5' ends is observed not only at actively transcribed genes but also at inactive loci. Mutagenesis of a typical promoter revealed a 22 bp segment of DNA sufficient to program formation of a NFR flanked by two H2A.Z nucleosomes. This segment contains a binding site of the Myb-related protein Reb1 and an adjacent dT:dA tract. Efficient deposition of H2A.Z is further promoted by a specific pattern of histone H3 and H4 tail acetylation and the bromodomain protein Bdf1, a component of the Swr1 remodeling complex that deposits H2A.Z.

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The yeast MAPK pathways required for mating versus filamentous growth share multiple components yet specify distinct programs. The mating-specific MAPK, Fus3, prevents crosstalk between the two pathways by unknown mechanisms. Here we show that pheromone signaling induces Fus3-dependent degradation of Tec1, the transcription factor specific to the filamentation pathway. Degradation requires Fus3 kinase activity and a MAPK phosphorylation site in Tec1 at threonine 273. Fus3 associates with Tec1 in unstimulated cells, and active Fus3 phosphorylates Tec1 on T273 in vitro. Destruction of Tec1 requires the F box protein Dia2 (Digs-into-agar-2), and Cdc53, the Cullin of SCF (Skp1-Cdc53-F box) ubiquitin ligases. Notably, mutation of the phosphoacceptor site in Tec1, deletion of FUS3, or deletion of DIA2 results in a loss of signaling specificity such that pheromone pathway signaling erroneously activates filamentation pathway gene expression and invasive growth. Signal-induced destruction of a transcription factor for a competing pathway provides a mechanism for signaling specificity.

In Saccharomyces cerevisiae, the pheromone-induced ubiquitylation and degradation of the filamentation pathway-specific activator, Tec1, suppresses cross talk between the mating and filamentous growth mitogenactivated protein kinase (MAPK) pathways. The mating pathway MAPK, Fus3, phosphorylates Tec1, resulting in its recognition by the SCF (for Skp1, Cullin, F-box containing) E3 ubiquitin ligase complex, leading to its proteolysis. Previously, it was found that Tec1 destruction requires phosphorylation on threonine 273 (T273). T273 is embedded in the sequence LLpTP, which is identical to the canonical binding site for Cdc4, a conserved F-box substrate adaptor for the SCF complex. However, recent work on both Cdc4 and the human Cdc4 ortholog Fbw7 has shown that a second substrate phosphorylation can be required for optimal Cdc4 binding in vitro. We report here that high-affinity binding of recombinant Cdc4 to Tec1 phosphopeptides requires phosphorylation of not only T273 but also a second site, T276. Significantly, both phospho-sites on Tec1 and a conserved basic pocket on Cdc4 are critical for Tec1 proteolysis in response to pheromone treatment of cells, establishing a role for two-phosphate recognition by yeast Cdc4 in substrate targeting in vivo.Cellular differentiation and survival depend on soliciting the correct intracellular response to environmental cues. Paradoxically, the signaling pathways in eukaryotic cells that perform these crucial functions often share components. How insulation of these interconnected signaling pathways is achieved to ensure a specific and accurate internal response to extracellular signals remains a central question in cell biology. In the budding yeast Saccharomyces cerevisiae, two conserved mitogen-activated protein kinase (MAPK) cascades share numerous components but regulate two distinct developmental programs, namely, mating and filamentous growth (FG). Each pathway contains a pathway-specific MAPK, Fus3 for the mating pathway and Kss1 for the FG pathway (6). However, since there are groups of shared components upstream and downstream of these pathway-specific kinases, additional mechanisms must exist to maintain signaling fidelity.In a significant advance for the field, one such mechanism has been reported that maintains signaling specificity between the mating and FG pathway. Specifically, we and others found that, upon activation of the mating pathway, the mating pathway-specific MAPK, Fus3, directs the destruction of the FG pathway-specific transcription factor, Tec1 (1, 2). During pheromone signaling, the FG pathway MAPK, Kss1, is activated, but the destruction of Tec1 prevents it from promoting transcription of FG pathway targets. Tec1 is phosphorylated by active Fus3, marking it as a substrate for the SCF ubiquitin ligase complex that in turn ubiquitylates Tec1 and targets it for proteolysis. This mechanism is operative under basal signaling conditions in the absence of pheromone (where receptor-independent signal transduction through the MAPK cascade occurs), as wel...

Developmental Cell was conceived nearly 15 years ago to provide a home for interdisciplinary work from a newly emerging overlap between cell biology and developmental biology, and it has grown along with these fields in the ensuing years. I joined the editorial team in 2009 and have had the pleasure of working with both Debbie Sweet and Dan Wainstock, the editorial staff at the journal's inception and the two preceding Editors of the journal. Under their leadership, the scope of Developmental Cell has evolved beyond the designations of ''in vivo cell biology'' and ''mechanistic studies of developmental biology'' to capture interdisciplinary studies straddling those and traditionally more molecular fields. It was my privilege to take on the role of Editor 6 months ago, and as the end of 2015 approaches, I wanted to share my perspective on the journal and our ongoing plans.The fundamental understanding of cell and developmental biology underlies many advances in human health and medicine. Yet, we are in a challenging time for basic research. Global stagnations in grant funding are paralleled by a shifting focus for many granting agencies and research institutes toward work with direct therapeutic relevance and applications. Here at Developmental Cell, we hold firm in our belief in the importance of basic insights into how living organisms are built, propagate, and respond to the environment, be it at the level of the cell, tissue, or the whole animal, in health or in disease. Since its founding, our journal has fostered work uncovering fundamental regulatory principles in cell and developmental biology. We aim not only to continue to provide a home for such exciting work but also to advocate for its importance to the understanding of disease and, ultimately, therapeutics. With this in mind, we are excited to present in this issue a Review article from Nilotpal Roy and Matthias Hebrok examining the role of cellular reprogramming-a key developmental process whose elucidation is reliant upon basic research and mouse models-in cancer progression.Remaining faithful to our founding principles, however, does not mean that we remain at a standstill. Scientific research is ever evolving, and so too must the journal's scope, lest we fall short in meeting the needs of our community and readership. The rapid growth in interdisciplinary work today is no longer just focused at the nexus of cell and developmental biology but also encompasses how these two areas interface with diverse fields ranging from metabolism and cancer biology to biomechanics and synthetic biology. We are excited to widen our reach to support work at these new crossroads. Research in these areas can help elucidate the minimum parts list of a cell biological process for synthetic biology applications (for example, work on endocytosis from David Drubin's group, published a few issues ago). Studies at these new crossroads can also shed light on the etiology of disease states that can then inform therapeutic development. For example, work bridging cell biology,...

Tumor cells co-opt fundamental cell biological and developmental processes in ingenious ways for their own benefit. Mutations and chromosomal rearrangements-detrimental in non-transformed cells-can promote proliferation and invasion in tumor cells. Niche cells that normally promote tissue homeostasis are engaged by tumor cells to promote their own maintenance. Cellular transitions that accompany normal development, such as the epithelial-to-mesenchymal transition, are re-deployed by cancer cells to promote invasion and metastasis. These are just a few examples of the many ways processes fundamental to cellular and organismal function are subverted during cancer progression.Recent research has greatly advanced our understanding of these processes and their relative contributions to tumorigenesis. In this issue, we are pleased to present a series of articles highlighting some of the latest insights into cancer cell biology, with a particular focus on mechanisms of metastasis. The articles cover a range of topics, from tumor intrinsic factors promoting invasion to extrinsic factors supporting tumor cells at each step of the metastatic progression.A Perspective from Gina LoMastro and Andrew Holland examines emerging work on the relationship between centrosome aberrations and invasion. The epithelial-to-mesenchymal transition and its role in promoting invasive and metastatic behaviors are explored in a Commentary from Rik Derynck and Robert Weinberg and in a Review from Wei Lu and Yibin Kang. A Review from Valerie Weaver and colleagues discusses how the extracellular matrix supports the tumor cell at multiple points, from growth and survival to migration and extravasation. David Lyden and colleagues, in a Review on the role of exosomes, examine how communication between primary tumors and distant organs mediates the establishment of the pre-metastatic niche and drives metastasis. Expanding on this theme, Xiang Zhang and colleagues explore tumor and organ-specific factors that determine the bias of different tumors to metastasize to specific organs. Finally, a Perspective from Ross Cagan, Leonard Zon, and Richard White highlights the significant contributions that research using zebrafish and Drosophila model systems have made and continue to make toward our understanding of the tumorigenic process and toward the development of cancer therapeutics. The Focus also includes a few shorter pieces (Spotlights and Previews) describing in more detail specific recent papers in the field.Together these articles underline the remarkable progress that is being made in our understanding of the tumorigenic process. Furthermore, they bring hope that through the targeting of the fundamental factors, pathways, and cells described in these reviews, effective therapies may be developed to inhibit cancer cells at each step of the metastatic process.We thank all the authors who have contributed their efforts and insights to this issue, and we hope you will find the articles engaging and stimulating.

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The cover of the first issue of Developmental Cell featured the application of FRET in living cells to study the cascade of protein interactions that occur during a wave of active receptor transport. Looking back, there couldn't have been a better illustration of the aim of the journal: providing a home for work that tackles, often through technically innovative approaches, the fundamentals of cell biological processes that ultimately orchestrate not just how an organism develops but also how it functions throughout its lifetime. Fifteen years on, the specific questions that engage the wide arenas of cell and developmental biology research may have shifted, but the fundamental hows and whys these questions stem from-that continue to inspire new work-remain much in the spirit of those addressed by the studies in the inaugural issue. How is cell identity determined and regulated? How does a cell communicate with its neighbors to form a tissue? How does a complex mix of cell types come together to form a living, breathing organism and allow it to thrive?In the past decade and a half, advances in the understanding of basic principles, along with technological developments that opened new avenues of inquiry, have given us fresh ways to frame our thinking. Thus, to celebrate the 15 th anniversary of Developmental Cell, we are excited to highlight a selection of areas where new perspectives have been brought to bear on crucial questions in cell and developmental biology.In many ways, the predominant challenges facing basic science research are ones of scale and resolution, and being able to go beyond just taking static snapshots of responses to single perturbations. The influx of approaches from other disciplines like physics, mathematics, and engineering, along with leaps in the technology for visualizing, measuring, perturbing, and recreating cellular events, has freed cell and developmental biologist to really pursue (to quote David Bilder from his Forum in this issue) ''the general study of how cells behave in response to both intrinsic gene expression and extrinsic signals from neighbors and the broader environment.''The Forum, Commentary, Perspective, and Review articles in this special issue tackle just this arena of general study. Focusing on intrinsic control of cell behavior, a Review from Matteo Perino and Gert Jan Veenstra discusses recent insights into the regulation of cell identity and thus developmental plasticity at the level of chromatin dynamics and organization, whereas a Forum piece from Kevin Chalut and Ewa Paluch highlights the emerging understanding of the role that the actin cortex has in bridging the dynamic mechanical changes in cell shape to cell function. It's no surprise that advances in both of these topics have been strongly influenced by respective contributions from biochemical mechanistic work in chromatin biology and biophysical work in cellular mechanics. Continuing on this thread of synergy with other disciplines, Commentaries from Yohanns Bellaiche and from Enrico Coen and Alexandr...