Search

Obesity and associated metabolic complications, including diabetes, cardiovascular and hepatic diseases, and certain types of cancers, create a major socioeconomic burden. Obesity is characterized by excessive expansion of white adipose tissue resulting from increased adipocyte size, and enhanced adipocyte precursor cells proliferation and differentiation into mature adipocytes, a process well-defined as adipogenesis. Efforts to develop therapeutically potent strategies to circumvent obesity are impacted by our limited understanding of molecular mechanisms regulating adipogenesis. In this review, we discuss recently discovered molecular mechanisms restraining adipogenesis. In this perspective, the discoveries of white adipose tissue endogenous adipogenesis-regulatory cells (Aregs) that negatively regulate adipocyte differentiation, platelet-derived growth factor receptor isoform α (PDGFRα) activation and downstream signaling that hinder adipocyte precursors differentiation, and a group of obesity-associated non-coding RNAs (ncRNAs) that regulate adipogenesis open up promising therapeutic avenues to prevent and/or treat obesity.

Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) (YAP/TAZ) are transcriptional coactivators that regulate genes involved in proliferation and transformation by interacting with DNA-binding transcription factors. Remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, and metastasis. The oncogenic activity of YAP/TAZ is inhibited by the Hippo cascade, an evolutionarily conserved pathway that is governed by two kinases, mammalian Ste20-like kinases 1/2 (MST1/2) and Large tumor suppressor kinase 1/2 (LATS1/2), corresponding to Drosophila's Hippo (Hpo) and Warts (Wts), respectively. One of the most influential aspects of YAP/TAZ biology is that these factors are transducers of cell structural features, including polarity, shape, and cytoskeletal organization. In turn, these features are intimately related to the cell's ability to attach to other cells and to the surrounding extracellular matrix (ECM), and are also influenced by the cell's microenvironment. Thus, YAP/TAZ respond to changes that occur at the level of whole tissues. Notably, small GTPases act as master organizers of the actin cytoskeleton. Recent studies provided convincing genetic evidence that small GTPase signaling pathways activate YAP/TAZ, while the Hippo pathway inhibits them. Biochemical studies showed that small GTPases facilitate the YAP-Tea domain transcription factor (TEAD) interaction by inhibiting YAP phosphorylation in response to serum stimulation, while the Hippo pathway facilitates the YAP-RUNX3 interaction by increasing YAP phosphorylation. Therefore, small GTPase pathways activate YAP/TAZ by switching its DNA-binding transcription factors. In this review, we summarize the relationship between the Hippo pathway and small GTPase pathways in the regulation of YAP/TAZ.

Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and Cdc42 are major modulators of the cytoskeleton. (N-)WASP and WIP control Rho GTPase activity in various cell types, either by direct WIP/(N-)WASP/Cdc42 or potential WIP/RhoA binding, or through secondary links that regulate GTPase distribution and/or transcription levels. WIP helps to regulate filopodium generation and participates in the Rac1-mediated ruffle formation that determines cell motility. In neurons, lack of WIP increases dendritic spine size and filamentous actin content in a RhoA-dependent manner. In contrast, WIP deficiency in an adenocarcinoma cell line significantly reduces RhoA levels. These data support a role for WIP in the GTPase-mediated regulation of numerous actin-related cell functions; we discuss the possibility that this WIP effect is linked to cell proliferative status.

Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination. Although the mechanisms regulating cell-cell communication remain unclear, recent findings indicate that it is based on acto-myosin cytoskeleton tension transmission from cell to cell through adherens junctions. As for single cell migration, small GTPases of the Rho and Rab families have been shown to be critical regulators of collective motion. Here, we discuss our current understanding on how these small GTPases are themselves regulated and how they control cell-cell communication during collective migration. Moreover, we also shed light on the key role of cell-cell communication and RhoGTPases in the physiological context of endothelial cell migration during angiogenesis.

Neutrophils in circulation experience significant shear forces due to blood flow when they tether to the vascular endothelium. Biochemical and biophysical responses of neutrophils to the physical force of flowing blood modulate their behavior and promote tissue recruitment under pro-inflammatory conditions. Neutrophil mechanotransduction responses occur through mechanisms that are not yet fully understood. In our recent work, we showed that GEF-H1, a RhoA specific guanine nucleotide exchange factor (GEF), is required to maintain neutrophil motility and migration in response to shear stress. GEF-H1 re-localizes to flottilin-rich uropods in neutrophils in response to fluid shear stress and promotes spreading and crawling on activated endothelial cells. GEF-H1 drives cellular contractility through myosin light chain (MLC) phosphorylation downstream of the Rho-ROCK signaling axis. We propose that GEF-H1-dependent cell spreading and crawling in shear stress-dependent neutrophil recruitment from the vasculature are due to the specific localization of Rho-induced contractility in the uropod.

Rap1 belongs to the Ras family of small GTPases, which are involved in a multitude of cellular signal transduction pathways and have extensively been linked to cancer biogenesis and metastasis. The small GTPase is activated in response to various extracellular and intracellular cues. Rap1 has conserved functions in Dictyostelium discoideum amoeba and mammalian cells, which are important for cell polarity, substrate and cell-cell adhesion and other processes that involve the regulation of cytoskeletal dynamics. Moreover, our recent study has shown that Rap1 is required for the formation of the replication-permissive vacuole of an intracellular bacterial pathogen. Here we review the function and regulation of Rap1 in these distinct processes, and we discuss the underlying signal transduction pathways.

Much of our current knowledge of Rho GTPase networks and the regulation by Rho guanine exchange factors (Rho GEFs) and Rho GTPase activating proteins (Rho GAPs) is based on population-based techniques. Over the last decades, technologies that enable single cell analysis with high spatial and temporal resolution have revealed that Rho GTPase activity in cells is regulated on second timescales and at submicrometer length scales. Therefore, perturbation methods with matching spatial and temporal resolution are crucial to further our understanding of Rho GTPase signaling. Here, we give a brief overview of the components of Rho GTPase signaling networks and review a range of existing perturbation strategies that target a specific component of the Rho GTPase signaling module. The advantages and limitations of each perturbation method are discussed. Several recommendations are formulated to guide future studies aimed at addressing spatiotemporal aspects of Rho GEF and Rho GTPase signaling.

Neutrophils are short-lived, abundant peripheral blood leukocytes that provide a first line of defense against bacterial and fungal infections whilst also being a key part of the inflammatory response. Chemokines induce neutrophil recruitment to inflammatory sites, where neutrophils perform a number of diverse functions that are aimed at fighting infections. Neutrophil effector functions are tightly regulated processes that are governed by an array of intracellular signaling pathways and initiated by receptor-ligand binding events. Dysregulated, neutrophil activation can result in excessive inflammation and host damage, as is evident in a number of autoimmune diseases. Rho family small GTPases and agonist-activated phosphoinositide 3-kinases (PI3Ks) represent two classes of key regulators of the highly specialized neutrophil. Here we review cross-talk between these important signaling intermediates in the context of neutrophil functions. We include PI3K-dependent activation of Rho family small GTPases and of their guanine nucleotide exchange factors and GTPase activating proteins, as well as Rho GTPase-dependent regulation of PI3K.

Spir actin nucleators and myosin V motor proteins were recently discovered to coexist in a protein complex. The direct interaction allows the coordinated activation of actin motor proteins and actin filament track generation at vesicle membranes. By now the cooperation of myosin V (MyoV) motors and Spir actin nucleation function has only been shown in the exocytic transport of Rab11 vesicles in metaphase mouse oocytes. Next to Rab11, myosin V motors however interact with a variety of Rab GTPases including Rab3, Rab8 and Rab10. As a common theme most of the MyoV interacting Rab GTPases function at different steps along the exocytic transport routes. We here summarize the different transport functions of class V myosins and provide as proof of principle data showing a colocalization of Spir actin nucleators and MyoVa at Rab8a vesicles. This suggests that besides Rab11/MyoV transport also the Rab8/MyoV and possibly other MyoV transport processes recruit Spir actin filament nucleation function.

Rho family GTPase signaling regulates the actin cytoskeleton and is critical for behaviors that range from the cell to tissue-scale. A theme in Rho GTPase biology is that there are many more regulators, such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), than GTPases themselves. Here, we review different, modular cases where GEFs and GAPs function together to elicit precise spatial and temporal control of signaling. We focus on examples from metazoan development, where precise regulation of Rho GTPases is critical for proper tissue form and function.

Tissue cells continually monitor anchorage conditions by gauging the physical properties of their underlying matrix and surrounding environment. The Rho and Ras GTPases are essential components of these mechanosensory pathways. These molecular switches control both cytoskeletal as well as cell fate responses to anchorage conditions and are thus critical to our understanding of how cells respond to their physical environment and, by extension, how malignant cells gainsay these regulatory pathways. Recent studies indicate that 2 proteins produced by the SHC1 gene, thought for the most part to functionally oppose each other, collaborate in their ability to respond to mechanical force by initiating respective Rho and Ras signals. In this review, we focus on the coupling of Shc and GTPases in the cellular response to mechanical anchorage signals, with emphasis on its relevance for cancer.

Together with a cyclin-dependent kinase (CDK) partner G1 cyclins control cell cycle entry by phosphorylating a number of nuclear targets and releasing a transcriptional program at the end of G1 phase. Yeast G1 cyclins also operate on cytoplasmic targets involved in the polarization of the cytoskeleton and vesicle trafficking. These processes are mainly controlled by the small GTPase Cdc42, and G1 cyclins regulate the activity of this and other small GTPases through the modulation of their regulators and effectors. This regulation is key for different developmental outcomes in unicellular organisms. In mammalian cells cytoplasmic G1 cyclin D1 has been shown to promote the activity of Rac1 and Ral GTPases and to block RhoA. Regulation of these small GTPases by G1 cyclins may constitute a mechanism to coordinate proliferation with cell migration and morphogenesis, important processes not only during normal development and organogenesis but also for tumor formation and metastasis. Here we briefly review the evidence supporting a role of G1 cyclins and CDKs as regulators of the activity of small GTPases, emphasizing their functional relevance both in budding yeast and in mammalian cells. This work was funded by Spanish Ministry of Education and Science (BFU2013-42895) from the Spanish Ministry of Economy and Competitivity and Catalan Government (SGR-559). T. Cemeli and MV Monserrat were supported by predoctoral fellowships from Spanish Ministry of Education and Science (FPU) and from University of Lleida, respectively.

Rab proteins regulate vesicular transport in eukaryotic cells and establish connections to various cellular structures and processes by interacting with so-called effector molecules. Several of these effectors are known to not only bind a single Rab protein, but to be able to bind multiple different Rabs simultaneously. In this review we will give a short overview of effectors in general and (putative) functions of the aforementioned multivalent Rab:effector interactions.

Rab35 and the Rab35 network of GAPs, GEFs, and effectors are important regulators of membrane trafficking for a variety of cellular processes, from cytokinesis and phagocytosis to neurite outgrowth. In the past five years, components of this signaling network have also been implicated as critical mediators of synaptic vesicle (SV) recycling and protein homeostasis. Recent studies by several groups, including our own, have demonstrated that Rab35-mediated endosomal sorting is required for the degradation of SV proteins via the ESCRT pathway, thereby eliminating old or damaged proteins from the SV pool. This sorting process is regulated by Rab35 activation in response to neuronal activity, and potentially by an antagonistic signaling relationship between Rab35 and the small GTPase Arf6 that directs SVs into distinct recycling pathways depending on neuronal activity levels. Furthermore, mutations in genes encoding Rab35 regulatory proteins are emerging as causative factors in human neurologic and neurodegenerative diseases, consistent with their important roles in synaptic and neuronal health. Here, we review these recent findings and offer our perspective on how the Rab35 signaling network functions to maintain neurotransmission and synaptic fitness.

Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy. These mutations include activating mutations and gene fusions involving the guanine nucleotide exchange factor, VAV1, as well as activating and dominant negative mutations in the GTPases KRAS and RHOA, respectively. In addition to mutations directly affecting the GTPase pathway, TCR signaling mutations indirectly affecting Ras- and Rho-family GTPases involving genes such as CD28, FYN, LCK, and PLCG1 are also reviewed.