E-cadherin/β-catenin expression is conserved in human and rat erythropoiesis and marks stress erythropoiesis.

E-cadherin is a crucial regulator of epithelial cell-to-cell adhesion and an established tumor suppressor. Aside epithelia, E-cadherin expression marks the erythroid cell lineage during human but not mouse hematopoiesis. However, the role of E-cadherin in human erythropoiesis remains unknown.

E-Cadherin Expression Distinguishes Mouse from Human Hematopoiesis in the Basophil and Erythroid Lineages.

E-cadherin is a key regulator of epithelial cell-cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive.

Canonical Wnt: a safeguard and threat for erythropoiesis.

Myeloid dysplastic syndrome (MDS) reflects a preleukemic bone marrow (BM) disorder with limited treatment options and poor disease survival. As only a minority of MDS patients are eligible for curative hematopoietic stem cell transplantation, there is an urgent need to develop alternative treatment options. Chronic activation of Wnt/β-catenin has been implicated to underlie MDS formation and recently assigned to drive MDS transformation to acute myeloid leukemia.

Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms.

Invasive lobular carcinoma (ILC) accounts for 8%-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation.

Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin.

E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina.

Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.

Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1.

PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma.

Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype.

Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland.

Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events in tumorigenesis remains challenging and requires in vivo validation studies in reliable animal models of human cancer. In this study, we describe a novel strategy for in vivo validation of candidate tumor suppressors implicated in invasive lobular breast carcinoma (ILC), which is hallmarked by loss of the cell-cell adhesion molecule E-cadherin.

Rac1 acts in conjunction with Nedd4 and dishevelled-1 to promote maturation of cell-cell contacts.

The Rho-GTPase Rac1 promotes actin polymerization and membrane protrusion that mediate initial contact and subsequent maturation of cell-cell junctions. Here we report that Rac1 associates with the ubiquitin-protein ligase neural precursor cell expressed developmentally down-regulated 4 (Nedd4). This interaction requires the hypervariable C-terminal domain of Rac1 and the WW domains of Nedd4.

Ubiquitin links to cytoskeletal dynamics, cell adhesion and migration.

Post-translational modifications are used by cells to link additional information to proteins. Most modifications are subtle and concern small moieties such as a phosphate group or a lipid. In contrast, protein ubiquitylation entails the covalent attachment of a full-length protein such as ubiquitin.

Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome.

Shwachman-Diamond Syndrome (SDS) is a rare inherited disease caused by mutations in the SBDS gene. Hematopoietic defects, exocrine pancreas dysfunction and short stature are the most prominent clinical features. To gain understanding of the molecular properties of the ubiquitously expressed SBDS protein, we examined its intracellular localization and mobility by live cell imaging techniques.

The F-BAR domain protein PACSIN2 associates with Rac1 and regulates cell spreading and migration.

The Rac1 GTPase controls cytoskeletal dynamics and is a key regulator of cell spreading and migration mediated by signaling through effector proteins, such as the PAK kinases and the Scar and WAVE proteins. We previously identified a series of regulatory proteins that associate with Rac1 through its hypervariable C-terminal domain, including the Rac1 activator β-Pix (also known as Rho guanine-nucleotide-exchange factor 7) and the membrane adapter caveolin-1. Here, we show that Rac1 associates, through its C-terminus, with the F-BAR domain protein PACSIN2, an inducer of membrane tubulation and a regulator of endocytosis.

The role of ubiquitylation and degradation in RhoGTPase signalling.

Rho-like guanosine triphosphatases (RhoGTPases) control many aspects of cellular physiology through their effects on the actin cytoskeleton and on gene transcription. Signalling by RhoGTPases is tightly coordinated and requires a series of regulatory proteins, including guanine-nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine-nucleotide dissociation inhibitors (GDIs). GEFs and GAPs regulate GTPase cycling between the active (GTP-bound) and inactive (GDP-bound) states, whereas GDI is a cytosolic chaperone that binds inactive RhoGTPases.

A model for phospho-caveolin-1-driven turnover of focal adhesions.

The regulation of Focal Adhesion (FA) dynamics is a key aspect of cellular motility. FAs concentrate integrins and associated cytoskeletal elements as well as a large number of regulatory proteins, including adapters, kinases and small GTPases of the Rho Family. We have recently shown that activated Rac1 can localize to FAs and can initiate the accumulation of the adapter protein Caveolin1 (Cav1) at FAs.

Focal-adhesion targeting links caveolin-1 to a Rac1-degradation pathway.

Directional cell migration is crucially dependent on the spatiotemporal control of intracellular signalling events. These events regulate polarized actin dynamics, resulting in protrusion at the front of the cell and contraction at the rear. The actin cytoskeleton is regulated through signalling by Rho-like GTPases, such as RhoA, which stimulates myosin-based contractility, and CDC42 and Rac1, which promote actin polymerization and protrusion.

Multi-transcriptional profiling of melanin-concentrating hormone and orexin-containing neurons.

1.Melanin-concentrating hormone (MCH) and orexin-containing neurons participate in hypothalamic circuits that control energy homeostasis. While these two systems have projections to widespread target areas within the central nervous system, little is known about intrinsic characteristics and the molecular composition of both the MCH and orexin neurons themselves.

Retroviral superinfection resistance.

The retroviral phenomenon of superinfection resistance (SIR) defines an interference mechanism that is established after primary infection, preventing the infected cell from being superinfected by a similar type of virus. This review describes our present understanding of the underlying mechanisms of SIR established by three characteristic retroviruses: Murine Leukaemia Virus (MuLV), Foamy Virus (FV), and Human Immunodeficiency Virus (HIV). In addition, SIR is discussed with respect to HIV superinfection of humans.