Herpes simplex virus type 1 (HSV-1) has been known as a common viral pathogen that can infect several parts of the body, leading to various clinical manifestations. According to this diverse manifestation, HSV-1 infection in many cell types was demonstrated. Besides the HSV-1 cell tropism, e.g., fibroblast, epithelial, mucosal cells, and neurons, HSV-1 infections can occur in human T lymphocyte cells, especially in activated T cells. In addition, several studies found that actin polymerization and filopodia formation support HSV-1 infection in diverse cell types. Hence, the goal of this review is to explore the mechanism of HSV-1 infection in various types of cells involving filopodia formation and highlight potential future directions for HSV-1 entry-related research. Moreover, this review covers several strategies for possible anti-HSV drugs focused on the entry step, offering insights into potential therapeutic interventions.

Bone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary.
The transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients\' tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays.
We elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actinin-1 to form α-Actinin-2:α-Actinin-4 complexes in GC cells. Moreover, NF-κB subunit RelA and α-Actinin-2 formed heterotrimers in the nuclei of GC cells. As a direct target of RelA:α-Actinin-2 heterotrimers, the ACTN2 gene was a positive auto-regulatory loop for α-Actinin-2 expression.
We demonstrated a link between filopodia, BMM and ACTN2 activation, where a feedforward activation loop between ACTN2 and RelA is established via actin in response to distant metastasis. Given the novel filopodia formation function and the new mechanism of BMM in GC, we propose ACTN2 as a druggable molecular vulnerability that may provide potential therapeutic benefit against BMM of GC.

Stroke stands as one of the most common causes of death among adults worldwide. Currently, tissue plasminogen activator serves as the only approved drug by the Food and Drug Administration for the treatment of acute ischemic stroke. Stem cell therapy serves as a viable treatment option and has been deemed as a safe and effective treatment for stroke patients. Adult human bone marrow-derived NCS-01 cells serve as a potential treatment for stroke given their ability to reduce stroke-induced pathological deficits by increasing cell viability and mitochondrial activity. Recently, we demonstrated the use of adult bone marrow-derived NCS-01 cells both on both in vitro and in vivo models. Using NCS-01 cells in rat stroke models subjected to middle cerebral artery occlusion, an effective dosage of 7.5 × 106 cells/ml, administered through the intracarotid artery within 3 days poststroke, was shown to display significant improvements in motor and neurological behaviors, reductions in infarct area, and peri-infarct cell loss. NCS-01 cells, in comparison with other lines of stem cells (Li cells), are shown to produce greater therapeutic effects, most likely due to the observed filopodia formation that allows the stem cells to extend and target the ischemic cells. Given these findings, NCS-01 stem cells serve as a potential treatment for stroke through the demonstration of profound efficacy and further research that favors their filopodia-mediated mechanism of action.

PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENβ. Here, we report the identification of PTENε (also named as PTEN5), a novel N-terminal-extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5\'UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions.

Flow-induced platelet activation prompts complex filopodial formation. Continuum methods fail to capture such molecular-scale mechanisms. A multiscale numerical model was developed to simulate this activation process, where a Dissipative Particle Dynamics (DPD) model of viscous blood flow is interfaced with a Coarse Grained Molecular Dynamics (CGMD) platelet model. Embedded in DPD blood flow, the macroscopic dynamic stresses are interactively transferred to the CGMD model, inducing intra-platelet associated events. The platelets activate by a biomechanical transductive linkage chain and dynamically change their shape in response. The models are fully coupled via a hybrid-potential interface and multiple time-stepping (MTS) schemes for handling the disparity between the spatiotemporal scales. Cumulative hemodynamic stresses that may lead to platelet activation are mapped on the surface membrane and simultaneously transmitted to the cytoplasm and cytoskeleton. Upon activation, the flowing platelets lose their quiescent discoid shape and evolve by forming filopodia. The model predictions were validated by a set of in vitro experiments, Platelets were exposed to various combinations of shear stresses and durations in our programmable hemodynamic shearing device (HSD). Their shape change was measured at multiple time points using scanning electron microscopy (SEM). The CGMD model parameters were fine-tuned by interrogating a parameter space established in these experiments. Segmentation of the SEM imaging streams was conducted by a deep machine learning system. This model can be further employed to simulate shear mediated platelet activation thrombosis initiation and to study the effects of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways.

Filopodia are slender actin-rich plasma membrane protrusions that function to drive cell migration and invasion. Despite the observation of defective filopodia formation in many malignant tumors, the regulation mechanism remained unknown to date. In the present study, for the first time, we demonstrate that RAB5A, a Rab GTPase family protein, is a potent regulator of filopodia formation in pancreatic cancer cells. High expression of RAB5A was associated with filopodia formation and migration in pancreatic cancer cells. Overexpression of RAB5A promoted filopodia formation and migration in CF Pac-1 cells. In contrast, down-regulation of RAB5A expression in SW1990 cells with a high endogenous RAB5A expression level impeded the formation of filopodia. Further analysis indicated that RAB5A was required for cdc42 activation in CF Pac-1 and SW1990 cells. Moreover, to investigate the underlying mechanism by which the activation of cdc42 mediates RAB5A-induced filopodia formation, the active state of β1-integrin was examined in cells with different expression levels of RAB5A. We observed that RAB5A regulated the accumulation of the active β1-integrin. We demonstrated that down-regulation of the expression of β1-integrin strongly suppressed filopodia formation and cdc42 activation mediated by RAB5A. These results indicate the important role of RAB5A in the regulation of filopodia formation in pancreatic cancer cells, which is dependent on the activation of cdc42 and β1-integrin.

The aim of this study was to examine the effect of bisphenol A (BPA) on the proliferation and motility potential of murine LM8 osteosarcoma cells.
LM8 cells were treated for 3 days with or without 80 μM BPA. The effect of BPA on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2\'-deoxyuridine (BrdU) incorporation study. Ethanol-fixed cells were stained with hematoxylin-eosin (H&E) to visualize cell morphology. Cell motility was assayed using inserts with uncoated membranes in invasion chambers. Expression of cell division cycle 42 (CDC42) was determined by immunofluorescence staining and western blotting.
BPA reduced the DNA content of cultures and the number of BrdU-positive cells. BPA induced a change in morphology from cuboidal with multiple filopodia on the cell surface to spindle-shaped with a smooth cell surface. BPA-treated cells expressed less CDC42 and were less motile than untreated cells.
BPA inhibited DNA replication and cell proliferation. BPA inhibited filopodia formation and motile potential by inhibiting CDC42 expression in LM8 cells.

We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) plays a crucial role in the promotion of migration of breast cancer cells. Lamellipodia and filopodia protrusions play fundamental roles, involving dynamic cytoskeleton reorganization in the metastasis of cancer. Here, we observed that the expression levels of both HBXIP and Calpain small subunit 1 (Capn4) were very high in clinical metastatic lymph nodes of breast tumor. Then, we found that HBXIP was able to up-regulate Capn4 at the levels of promoter, mRNA and protein in breast cancer cells through activation of ERK1/2. Moreover, we showed that HBXIP activated ERK1/2 through up-regulating MEKK2. In function, we revealed that HBXIP increased the filopodia formation through Capn4, resulting in cell migration. Thus, we conclude that the oncoprotein HBXIP enhances the migration of breast cancer through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Therapeutically, HBXIP may serve as a novel target in breast cancer.

Neuronal glycoprotein M6a is involved in neuronal plasticity, promoting neurite and filopodia outgrowth and, likely, synaptogenesis. Polymorphisms in the human M6a gene GPM6A have recently been associated with mental illnesses such as schizophrenia, bipolar disorders, and claustrophobia. Nevertheless, the molecular bases underlying these observations remain unknown. We have previously documented that, to induce filopodia formation, M6a depends on the association of membrane lipid microdomains and the activation of Src and mitogen-activated protein kinase kinases. Here, in silico analysis of the phosphorylation of tyrosine 251 (Y251) at the C-terminus of M6a showed that it could be a target of Src kinases. We examined whether phosphorylation of M6a at Y251 affects neurite and filopodia outgrowth and the targets involved in its signal propagation. This work provides evidence that the Src kinase family and the phosphatidylinositide 3-kinase (PI3K), but not Ras, participate in M6a signal cascade leading to neurite/filopodia outgrowth in hippocampal neurons and murine neuroblastoma N2a cells. Phosphorylation of M6a at Y251 is essential only for neurite outgrowth by the PI3K/AKT-mediated pathway and, moreover, rescues the inhibition caused by selective Src inhibitor and external M6a monoclonal antibody treatment. Thus, we suggest that phosphorylation of M6a at Y251 is critical for a specific stage of neuronal development and triggers redundant signaling pathways leading to neurite extension.

Formins are an important and evolutionarily well conserved class of actin binding proteins with essential biological functions. Although their molecular roles in actin regulation have been clearly demonstrated in vitro, their functions at the cellular or organism levels are still poorly understood. To illustrate this problem, but also to demonstrate potential ways forward, we focus here on the DAAM group of formins. In vertebrates, DAAM group members have been demonstrated to be important regulators of cellular and tissue morphogenesis but, as for all formins, the molecular mechanisms underlying these morphogenetic functions remain to be uncovered. The genome of the fruitfly Drosophila encodes a single DAAM gene that is evolutionarily highly conserved. Recent work on dDAAM has already provided a unique combination of observations and experimental opportunities unrivalled by any other Drosophila formin. These comprise in vitro actin polymerisation assays, subcellular studies in culture and in vivo, and a range of developmental phenotypes revealing a role in tracheal morphogenesis, axonal growth and muscle organization. At all these levels, future work on dDAAM will capitalize on the power of fly genetics, raising unique opportunities to advance our understanding of dDAAM at the systems level, with obvious implications for other formins.