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RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.

ABSTRACT: During angiogenesis, VEGF acts as an attractive cue for endothelial cells (ECs), while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCγ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

SUBMITTER: Fukushima Y

PROVIDER: S-EPMC7298304 | biostudies-literature |

REPOSITORIES: biostudies-literature

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RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells

Project description:During angiogenesis, VEGF acts an attractive cue for endothelial cells (ECs) while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ is released from PlexinD1 inducing cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCg, Erk and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ-deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

| S-SCDT-EMBOJ-2019-102930 | biostudies-other

Attractive serial dependence overcomes repulsive neuronal adaptation.

Project description:Sensory responses and behavior are strongly shaped by stimulus history. For example, perceptual reports are sometimes biased toward previously viewed stimuli (serial dependence). While behavioral studies have pointed to both perceptual and postperceptual origins of this phenomenon, neural data that could elucidate where these biases emerge is limited. We recorded functional magnetic resonance imaging (fMRI) responses while human participants (male and female) performed a delayed orientation discrimination task. While behavioral reports were attracted to the previous stimulus, response patterns in visual cortex were repelled. We reconciled these opposing neural and behavioral biases using a model where both sensory encoding and readout are shaped by stimulus history. First, neural adaptation reduces redundancy at encoding and leads to the repulsive biases that we observed in visual cortex. Second, our modeling work suggest that serial dependence is induced by readout mechanisms that account for adaptation in visual cortex. According to this account, the visual system can simultaneously improve efficiency via adaptation while still optimizing behavior based on the temporal structure of natural stimuli.

| S-EPMC9447932 | biostudies-literature

LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues.

Project description:Somatic inactivation of the serine/threonine kinase gene STK11/LKB1/PAR-4 occurs in a variety of cancers, including ∼10% of melanoma. However, how the loss of LKB1 activity facilitates melanoma invasion and metastasis remains poorly understood. In LKB1-null cells derived from an autochthonous murine model of melanoma with activated Kras and Lkb1 loss and matched reconstituted controls, we have investigated the mechanism by which LKB1 loss increases melanoma invasive motility. Using a microfluidic gradient chamber system and time-lapse microscopy, in this paper, we uncover a new function for LKB1 as a directional migration sensor of gradients of extracellular matrix (haptotaxis) but not soluble growth factor cues (chemotaxis). Systematic perturbation of known LKB1 effectors demonstrated that this response does not require canonical adenosine monophosphate-activated protein kinase (AMPK) activity but instead requires the activity of the AMPK-related microtubule affinity-regulating kinase (MARK)/PAR-1 family kinases. Inhibition of the LKB1-MARK pathway facilitated invasive motility, suggesting that loss of the ability to sense inhibitory matrix cues may promote melanoma invasion.

| S-EPMC4210439 | biostudies-literature

Arf6 in lymphatic endothelial cells regulates lymphangiogenesis by controlling directional cell migration.

Project description:The small GTPase Arf6 plays pivotal roles in a wide variety of cellular events such as endocytosis, exocytosis, and actin cytoskeleton reorganization. However, the physiological functions of Arf6 at the whole animal level have not yet been thoroughly understood. Here, we show that Arf6 regulates developmental and tumor lymphangiogenesis in mice. Lymphatic endothelial cell (LEC)-specific Arf6 conditional knockout (LEC-Arf6 cKO) mouse embryos exhibit severe skin edema and impairment in the formation of lymphatic vessel network at the mid-gestation stage. Knockdown of Arf6 in human LECs inhibits in vitro capillary tube formation and directed cell migration induced by vascular endothelial growth factor-C (VEGF-C) by inhibiting VEGF-C-induced internalization of ?1 integrin. Finally, we found that LEC-Arf6 cKO mice transplanted with B16 melanoma cells attenuated tumor lymphangiogenesis and progression. Collectively, these results demonstrate that Arf6 in LECs plays a crucial role in physiological and pathological lymphangiogenesis.

| S-EPMC5595869 | biostudies-other

Discontinuous nature of the repulsive-to-attractive colloidal glass transition.

Project description:In purely repulsive colloidal systems a glass transition can be reached by increasing the particle volume fraction beyond a certain threshold. The resulting glassy state is governed by configurational cages which confine particles and restrict their motion. A colloidal glass may also be formed by inducing attractive interactions between the particles. When attraction is turned on in a repulsive colloidal glass a re-entrant solidification ensues. Initially, the repulsive glass melts as free volume in the system increases. As the attraction strength is increased further, this weakened configurational glass gives way to an attractive glass in which motion is hindered by the formation of physical bonds between neighboring particles. In this paper, we study the transition from repulsive-to-attractive glasses using three-dimensional imaging at the single-particle level. We show how the onset of cage weakening and bond formation is signalled by subtle changes in local structure. We then demonstrate the discontinuous nature of the solid-solid transition, which is marked by a critical onset at a threshold bonding energy. Finally, we highlight how the interplay between bonding and caging leads to complex and heterogeneous dynamics at the microscale.

| S-EPMC4778135 | biostudies-other

Octopamine and tyramine respectively regulate attractive and repulsive behavior in locust phase changes.

Project description:Aggregative and solitary behaviors are universal phenomena in animals. Interestingly, locusts (Locusta migratoria) can reversibly transit their behavior between gregarious and solitary phase through conspecific attraction and repulsion. However, the regulatory mechanism of neurotransmitters underlying attraction and repulsion among locusts remains unknown. In this study, we found gregarious and solitary locusts were attracted or repulsed respectively by gregarious volatiles. Solitary locusts can transform their preference for gregarious volatiles during crowding, whereas gregarious locusts avoided their volatiles during isolation. During crowding and isolation, the activities of octopamine and tyramine signalings were respectively correlated with attraction- and repulsion-response to gregarious volatiles. RNA interference verified that octopamine receptor ? (OAR?) signaling in gregarious locusts controlled attraction-response, whereas in solitary ones, tyramine receptor (TAR) signaling mediated repulsion-response. Moreover, the activation of OAR? signaling in solitary locusts caused the behavioral shift from repulsion to attraction. Enhancement of TAR signaling in gregarious locusts resulted in the behavioral shift from attraction to repulsion. The olfactory preference of gregarious and solitary locusts co-injected by these two monoamines displayed the same tendency as the olfactory perception in crowding and isolation, respectively. Thus, the invertebrate-specific octopamine-OAR? and tyramine-TAR signalings respectively mediate attractive and repulsive behavior in behavioral plasticity in locusts.

| S-EPMC5389030 | biostudies-literature

Proteolytic activity of endothelial cells provides directional cues to shape bones

Project description:Proteolytic activity of endothelial cells provides directional cues to shape bones

| PRJEB27136 | ENA

Functional angiogenesis requires microenvironmental cues balancing endothelial cell migration and proliferation.

Project description:Angiogenesis is a complex morphogenetic process that involves intimate interactions between multicellular endothelial structures and their extracellular milieu. In vitro models of angiogenesis can aid in reducing the complexity of the in vivo microenvironment and provide mechanistic insight into how soluble and physical extracellular matrix cues regulate this process. To investigate how microenvironmental cues regulate angiogenesis and the function of resulting microvasculature, we multiplexed an established angiogenesis-on-a-chip platform that affords higher throughput investigation of 3D endothelial cell sprouting emanating from a parent vessel through defined biochemical gradients and extracellular matrix. We found that two fundamental endothelial cell functions, migration and proliferation, dictate endothelial cell invasion as single cells vs. multicellular sprouts. Microenvironmental cues that elicit excessive migration speed incommensurate with proliferation resulted in microvasculature with poor barrier function and an inability to transport fluid across the microvascular bed. Restoring the balance between migration speed and proliferation rate rescued multicellular sprout invasion, providing a new framework for the design of pro-angiogenic biomaterials that guide functional microvasculature formation for regenerative therapies.

| S-EPMC7328820 | biostudies-literature

Borg5 is required for angiogenesis by regulating persistent directional migration of the cardiac microvascular endothelial cells.

Project description:The microvasculature is important for vertebrate organ development and homeostasis. However, the molecular mechanism of microvascular angiogenesis remains incompletely understood. Through studying Borg5 (Binder of the Rho GTPase 5), which belongs to a family of poorly understood effector proteins of the Cdc42 GTPase, we uncover a role for Borg5 in microvascular angiogenesis. Deletion of Borg5 in mice results in defects in retinal and cardiac microvasculature as well as heart development. Borg5 promotes angiogenesis by regulating persistent directional migration of the endothelial cells (ECs). In primary mouse cardiac ECs (MCECs), Borg5 associates with septins in the perinuclear region and colocalizes with actomyosin fibers. Both Borg5 deletion and septin 7 knockdown lead to a disruption of the perinuclear actomyosin and persistent directional migration. Our findings suggest that Borg5 and septin cytoskeleton spatially control actomyosin activity to ensure persistent directional migration of MCECs and efficient microvascular angiogenesis. Our studies reported here should offer a new avenue to further investigate the functions of Borg5, septin, and actomyosin in the microvasculature in the context of development and disease.

| S-EPMC3952853 | biostudies-other

Attractive and repulsive residue fragments at the interface of SARS-CoV-2 and hACE2.

Project description:The initial stages of SARS-CoV-2 coronavirus attachment to human cells are mediated by non-covalent interactions of viral spike (S) protein receptor binding domains (S-RBD) with human ACE2 receptors (hACE2). Structural characterization techniques, such as X-ray crystallography (XRC) and cryoelectron microscopy (cryo-EM), previously identified SARS-CoV-2 spike protein conformations and their surface residues in contact with hACE2. However, recent quantum-biochemical calculations on the structurally related S-RBD of SARS-CoV-1 identified some contact-residue fragments as intrinsically attractive and others as repulsive. This indicates that not all surface residues are equally important for hACE2 attachment. Here, using similar quantum-biochemical methods, we report some four-residue fragments (i.e quartets) of the SARS-CoV-2 S-RBD as intrinsically attractive towards hACE2 and, therefore, directly promoting host-virus non-covalent binding. Other fragments are found to be repulsive although involved in intermolecular recognition. By evaluation of their respective intermolecular interaction energies we found two hACE2 fragments that include contact residues (ASP30, LYS31, HIS34) and (ASP38, TYR41, GLN42), respectively, behaving as important SARS-CoV-2 attractors. LYS353 also promotes viral binding via several mechanisms including dispersion van der Waals forces. Similarly, among others, three SARS-CoV-2 S-RBD fragments that include residues (GLN498, THR500, ASN501), (GLU484, PHE486, ASN487) and (LYS417), respectively, were identified as hACE2 attractors. In addition, key hACE2 quartets identified as weakly-repulsive towards the S-RBD of SARS-CoV-1 were found strongly attractive towards SARS-CoV-2 explaining, in part, the stronger binding affinity of hACE2 towards the latter coronavirus. These findings may guide the development of synthetic antibodies or identify potential viral epitopes.

| S-EPMC8206228 | biostudies-literature

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