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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.

The Citron protein was originally identified for its capability to specifically bind the active form of RhoA small GTPase, leading to the simplistic hypothesis that it may work as a RhoA downstream effector in actin remodeling. More than two decades later, a much more complex picture has emerged. In particular, it has become clear that in animals, and especially in mammals, the functions of the Citron gene (CIT) are intimately linked to many aspects of central nervous system (CNS) development and function, although the gene is broadly expressed. More specifically, CIT encodes two main isoforms, Citron-kinase (CIT-K) and Citron-N (CIT-N), characterized by complementary expression pattern and different functions. Moreover, in many of their activities, CIT proteins act more as upstream regulators than as downstream effectors of RhoA. Finally it has been found that, besides working through actin, CIT proteins have many crucial functional interactions with the microtubule cytoskeleton and may directly affect genome stability. In this review, we will summarize these advances and illustrate their actual or potential relevance for CNS diseases, including microcephaly and psychiatric disorders.

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.

The organisation of intracellular transport processes is adapted specifically to different cell types, developmental stages, and physiological requirements. Some protein traffic routes are universal to all cells and constitutively active, while other routes are cell-type specific, transient, and induced under particular conditions only. Small GTPases of the Rab (Ras related in brain) subfamily are conserved across eukaryotes and regulate most intracellular transit pathways. The complete sets of Rab proteins have been identified in model organisms, and molecular principles underlying Rab functions have been uncovered. Rabs provide intracellular landmarks that define intracellular transport sequences. Nevertheless, it remains a challenge to systematically map the subcellular distribution of all Rabs and their functional interrelations. This task requires novel tools to precisely describe and manipulate the Rab machinery in vivo. Here we discuss recent findings about Rab roles during development and we consider novel approaches to investigate Rab functions in vivo.

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.

Mutant RAS isoforms are the most common oncogenes affecting human cancers. After decades of effort in developing drugs targeting oncogenic RAS-driven cancers, we are still charting an unclear path. Despite recent developments exemplified by KRAS (G12C) inhibitors, direct targeting of mutant RAS remains a difficult endeavor. Inhibiting RAS function by targeting its post-translational prenylation processing has remained an important approach, especially with recent progress on the study of isoprenylcysteine carboxylmethyltransferase (ICMT), the unique enzyme for the last step of prenylation processing of RAS isoforms and other substrates. Inhibition of ICMT has shown efficacy both in vitro and in vivo in RAS-mutant cancer models. We will discuss the roles of RAS family of proteins in human cancers and the impact of post-prenylation carboxylmethylation on RAS driven tumorigenesis. In addition, we will review what is known of the molecular and cellular impact of ICMT inhibition on cancer cells that underlie its anti-proliferative and pro-apoptosis efficacy.

Local modulation of the actin cytoskeleton is essential for the initiation and maintenance of strong homotypic adhesive interfaces between neighboring cells. The epithelial adherens junction (AJ) fulfils a central role in this process by mediating E-cadherin interactions and functioning as a signaling scaffold to control the activity of the small GTPase RhoA and subsequent actomyosin contractility. Interestingly, a number of regulatory proteins that modulate RhoA activity at the AJ also control RhoA during cytokinesis, an actomyosin-dependent process that divides the cytoplasm to generate two daughter cells at the final stages of mitosis. Recent insights have revealed that the central player in AJ stability, p120-catenin (p120), interacts with and modulates essential regulators of actomyosin contraction during cytokinesis. In cancer, loss of this modulation is a common event during tumor progression that can induce chromosomal instability and tumor progression. In this review, we will highlight the functional differences and similarities of the different RhoA-associated factors that have been linked to both the regulation of cell-cell adhesion and cytokinesis.

Cool-associated tyrosine phosphorylated protein 1 (Cat1), also referred to as GPCR-kinase interacting protein 1 (Git1), is a ubiquitously expressed, multi-domain protein that is best known for regulating cell shape and migration. Cat1/Git1 functions as a GTPase activating protein (GAP) that inactivates certain members of the ADP-ribosylation factor (Arf) family of small GTPases. It is also a scaffold that brings together several signaling proteins at specific locations within the cell, ensuring their efficient activation. Here we will discuss what is known regarding the classical role of Cat1/Git1 in the regulation of cell morphology and migration, as well as highlight some more recent findings that suggest this interesting signaling/scaffolding protein may also contribute in unexpected ways to oncogenic transformation.

Members of the MYC family of proto-oncogenes are the most commonly deregulated genes in all human cancers. MYC proteins drive an increase in cellular proliferation and facilitate multiple aspects of tumor initiation and progression, thereby controlling all hallmarks of cancer. MYC's ability to drive metabolic reprogramming of tumor cells leading to biomass accumulation and cellular proliferation is the most studied function of these oncogenes. MYC also regulates tumor progression and is often implicated in resistance to chemotherapy and in metastasis. While most oncogenic functions of MYC are attributed to its role as a transcription factor, more recently, new roles of MYC as a pro-survival factor in the cytoplasm suggest a previously unappreciated diversity in MYC's roles in cancer progression. This review will focus on the role of MYC in invasion and will discuss the canonical functions of MYC in Epithelial to Mesenchymal Transition and the cytoplasmic functions of MYC-nick in collective migration.

The Arf and Rho subfamilies of small GTPases are nucleotide-dependent molecular switches that act as master regulators of vesicular trafficking and the actin cytoskeleton organization. Small GTPases control cell processes with high fidelity by acting through distinct repertoires of binding partners called effectors. While we understand a great deal about how these GTPases act individually, relatively little is known about how they cooperate, especially in the control of effectors. This review highlights how Arf GTPases collaborate with Rac1 to regulate actin cytoskeleton dynamics at the membrane via recruiting and activating the Wave Regulatory Complex (WRC), a Rho effector that underpins lamellipodia formation and macropinocytosis. This provides insight into Arf regulation of the actin cytoskeleton, while putting the spotlight on small GTPase cooperation with emerging evidence of its importance in fundamental cell biology and interactions with pathogenic bacteria.

Acute myeloid leukemia (AML) is a devastating malignancy for which novel treatment approaches are desperately needed. Ras signaling is an attractive therapeutic target for AML because a large proportion of AMLs have mutations in NRAS, KRAS, or genes that activate Ras signaling, and key Ras effectors are activated in virtually all AML patient samples. This has inspired efforts to develop Ras-targeted treatment strategies for AML. Due to the inherent difficulty and disappointing efficacy of targeting Ras proteins directly, many have focused on inhibiting Ras effector pathways. Inhibiting the major oncogenic Ras effectors, the mitogen-activated protein kinase (MAPK) and/or phosphatidylinositiol-3-kinase (PI3K) pathways, has generally demonstrated modest efficacy for AML. While this may be in part related to functional redundancy between these pathways, it is now clear that other Ras effectors have key oncogenic roles. Specifically, the Ras-like (Ral) GTPases have emerged as critical mediators of Ras-driven transformation and AML cell survival. Our group recently uncovered a critical role for RALB signaling in leukemic cell survival and a potential mediator of relapse following Ras-targeted therapy in AML. Furthermore, we found that RALB signaling is hyperactivated in AML patient samples, and inhibiting RALB has potent anti-leukemic activity in preclinical AML models. While key questions remain regarding the importance of RALB signaling across the genetically diverse spectrum of AML, the specific mechanism(s) that promotes leukemic cell survival downstream of RALB, and how to pharmacologically target RALB signaling effectively - RALB has emerged as a critical Ras effector and potential therapeutic target for AML.

Intracellular pathogens often exploit RAB functions to establish a safe haven in which to survive and proliferate. Ehrlichia chaffeensis, an obligatory intracellular bacterium, resides in specialized membrane-bound inclusions that have early endosome–like characteristics, e.g., resident RAB5 GTPase and RAB5 effectors, including VPS34 (the catalytic subunit of class III phosphatidylinositol 3-kinase), but the inclusions lack late endosomal or lysosomal markers. Within inclusions, Ehrlichia obtains host-derived nutrients by inducing RAB5-regulated autophagy using Ehrlichia translocated factor-1 deployed by its type IV secretion system. This manipulation of RAB5 by a bacterial molecule offers a simple strategy for Ehrlichia to avoid destruction in lysosomes and obtain nutrients, membrane components, and a homeostatic intra-host-cell environment in which to grow.

The superfamily of small monomeric GTPases originated in a common ancestor of eukaryotic multicellular organisms and, since then, it has evolved independently in each lineage to cope with the environmental challenges imposed by their different life styles. Members of the small GTPase family function in the control of vesicle trafficking, cytoskeleton rearrangements and signaling during crucial biological processes, such as cell growth and responses to environmental cues. In this review, we discuss the emerging roles of these small GTPases in the pathogenic and symbiotic interactions established by plants with microorganisms present in their nearest environment, in which membrane trafficking is crucial along the different steps of the interaction, from recognition and signal transduction to nutrient exchange., Instituto de Biotecnologia y Biologia Molecular

Post translational modifications of RUNX3 have been shown to play an important role in directing RUNX3 functions. In this review we highlight the phosphorylation dependent functions of RUNX3 as regulated by PAK1 and its implications on tumorigenesis.

The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. We recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation. Increased expression and activity of both HIFs and ROCK1 occurs in many types of cancer supporting the potential therapeutic role of ROCK inhibitors beyond CC-RCC. We also discuss future research required to establish prognostic markers to predict tumor response to ROCK inhibitors.

Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.

The exocyst complex mediates the tethering of secretory vesicles to the plasma membrane before SNARE-mediated membrane fusion. Recent studies have implicated the exocyst in a wide range of cellular processes. Particularly, research on the Exo70 subunit of the complex has linked the function of the exocyst in exocytosis to cell adhesion, migration and invasion. In this review, we will discuss the recent work on how Exo70 regulates these cellular processes, and how small GTPases and kinases interact with Exo70 to orchestrate its function in exocytosis and cytoskeleton organization. The study of Exo70 contributes to the understanding of many pathophysiological processes from organogenesis to cancer metastasis.

The specific and rapid formation of protein complexes, involving IQGAP family proteins, is essential for diverse cellular processes, such as adhesion, polarization, and directional migration. Although CDC42 and RAC1, prominent members of the RHO GTPase family, have been implicated in binding to and activating IQGAP1, the exact nature of this protein-protein recognition process has remained obscure. Here, we propose a mechanistic framework model that is based on a multiple-step binding process, which is a prerequisite for the dynamic functions of IQGAP1 as a scaffolding protein and a critical mechanism in temporal regulation and integration of cellular pathways.

Cell migration is central to many developmental, physiologic and pathological processes, including cancer progression. The Ral GTPases (RalA and RalB) which act down-stream the Ras oncogenes, are key players in the coordination between membrane trafficking and actin polymerization. A major direct effector of Ral, the exocyst complex, works in polarized exocytosis and is at the center of multiple protein-protein interactions that support cell migration by promoting protrusion formation, front-rear polarization, and extra-cellular matrix degradation. In this review we describe the recent advancements in deciphering the molecular mechanisms underlying this role of Ral via exocyst on cell migration. Among others, we will discuss the recently identified cross-talk between Ral and Rac1 pathways: exocyst binds to a negative regulator (the RacGAP SH3BP1) and to the major effector (the Wave Regulatory Complex, WRC) of Rac1, the master regulator of protrusions. Next challenge will be to better characterize the dynamics in space and in time of these molecular interplays, to better understand the pleiotropic functions of Ral in both normal and cancer cells.

Small GTPases play crucial roles in the maintenance of a homeostatic environment and appropriate movements of the cell. In these processes, the direct or indirect interaction between distinct small GTPases could be required for regulating mutual signaling pathways. In our recent study, ARHGEF10, known as a guanine nucleotide exchange factor (GEF) for RhoA, was indicated to interact with Rab6A and Rab8A, which are known to function in the exocytotic pathway, and colocalized with these Rabs at exocytotic vesicles. Moreover, it was suggested that ARHGEF10 is involved in the regulation of Rab6A and Rab8A localization and invasion of breast carcinoma cells, in which Rab8 also acts via regulation of membrane trafficking. These results may reveal the existence of a novel small GTPase cascade which connects the signaling of these Rabs with RhoA during membrane trafficking. In this mini-review, we consider the possible functions of ARHGEF10 and RhoA in the Rab6- and Rab8-mediated membrane trafficking pathway.

Although biosynthetic trafficking can function constitutively, it also functions specifically for certain developmental processes. These processes require either a large increase to biosynthesis or the biosynthesis and targeted trafficking of specific players. We review the conserved molecular mechanisms that direct biosynthetic trafficking, and discuss how their genetic disruption affects animal development. Specifically, we consider Arf small G proteins, such as Arf1 and Sar1, and their coat effectors, COPI and COPII, and how these proteins promote biosynthetic trafficking for cleavage of the Drosophila embryo, the growth of neuronal dendrites and synapses, extracellular matrix secretion for bone development, lumen development in epithelial tubes, notochord and neural tube development, and ciliogenesis. Specific need for the biosynthetic trafficking system is also evident from conserved CrebA/Creb3-like transcription factors increasing the expression of secretory machinery during several of these developmental processes. Moreover, dysfunctional trafficking leads to a range of developmental syndromes.

Cell migration, a key feature of embryonic development, immunity, angiogenesis, and tumor metastasis, is based on the coordinated regulation of actin dynamics and integrin-mediated adhesion. Rho GTPases play a major role in this phenomenon by regulating the onset and maintenance of actin-based protruding structures at cell leading edges (i.e. lamellipodia and filopodia) and contractile structures (i.e., stress fibers) at their trailing edge. While spatio-temporal analysis demonstrated the tight regulation of Rho GTPases at the migration front during cell locomotion, little is known about how the main regulators of Rho GTPase activity, such as GAPs, GEFs and GDIs, play a role in this process. In this review, we focus on a major negative regulator of RhoA, p190RhoGAP-A and its close isoform p190RhoGAP-B, which are necessary for efficient cell migration. Recent studies, including our, demonstrated that p190RhoGAP-A localization and activity undergo a complex regulatory mechanism, accounting for the tight regulation of RhoA, but also other members of the Rho GTPase family, at the cell periphery.

During macroautophagy, the phagophore-mediated formation of autophagosomes and their subsequent fusion with lysosomes requires extensive transformation of the endomembrane system. Membrane dynamics in eukaryotic cells is regulated by small GTPase proteins including Arfs and Rabs. The small GTPase proteins that regulate autophagic membrane traffic are mostly conserved in yeast and metazoans, but there are also several differences. In this mini-review, we compare the small GTPase network of yeast and metazoan cells that regulates autophagy, and point out the similarities and differences in these organisms.