Seeing with electrons

Building the complex architecture of tubular organs is a highly dynamic process that involves cell migration, polarization, shape changes, adhesion to neighboring cells and the extracellular matrix, physicochemical characteristics of the extracellular matrix and reciprocal signaling with the mesenchyme. Understanding these processes in vivo has been challenging as they take place over extended time periods deep within the developing organism. Here, I will discuss 3D in vitro models that have been crucial to understand many of the molecular and cellular mechanisms and key concepts underlying branching morphogenesis in vivo

Translating Membrane Tension into Cytoskeletal Action by FBP17

Item does not contain fulltextA recent article by Tsujita et al. (2015) in Nature Cell Biology provides insight into how cells sense and translate plasma membrane tension toward polarized actin polymerization and migration. They identify FBP17 as a multifunctional adaptor that senses membrane curvature and delivers feedback to actin dynamics and directed cell migration

Making Heads or Tails of It: Cell-Cell Adhesion in Cellular and Supracellular Polarity in Collective Migration

Collective cell migration is paramount to morphogenesis and contributes to the pathogenesis of cancer. To migrate directionally and reach their site of destination, migrating cells must distinguish a front and a rear. In addition to polarizing individually, cell-cell interactions in collectively migrating cells give rise to a higher order of polarity, which allows them to move as a supracellular unit. Rather than just conferring adhesion, emerging evidence indicates that cadherin-based adherens junctions intrinsically polarize the cluster and relay mechanical signals to establish both intracellular and supracellular polarity. In this review, we discuss the various functions of adherens junctions in polarity of migrating cohorts

Roles and Regulation of Epithelial Splicing Regulatory Proteins 1 and 2 in Epithelial-Mesenchymal Transition

Item does not contain fulltextThe transformation of polarized epithelial cells into cells with mesenchymal characteristics by the morphogenetic process of epithelial-mesenchymal transition (EMT) is a well-characterized process essential for embryonic development and associated with cancer progression. EMT is a program driven by changes in gene expression induced by several EMT-specific transcription factors, which inhibit the expression of cell-cell adhesion proteins and other epithelial markers, causing a characteristic loss of cell-cell adhesion, a switch to mesenchymal cell morphology, and increased migratory capabilities. Recently, it has become apparent that in addition to these transcriptionally regulated changes, EMT may also be regulated posttranscriptionally, that is, by alternative splicing. Specifically, the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) have been described as epithelial-specific splicing master regulators specifically involved in EMT-associated alternative splicing. Here, we discuss the regulation of ESRP activity, as well as the evidence supporting a causal role of ESRPs in EMT

Integration eller konvergens – spelar det någon roll?

Man kan tycka att det spelar mindre roll vad saker och ting kallas om man ändå får en känsla för vad det handlar om. Men så är det inte. Om vi väljer ”integration” som styrande princip kommer vi att försöka bygga integrerande bryggor mellan PLM, SE och CM. Om vi i stället väljer ”konvergens” kommer vi att sträva efter att PLM, SE och CM ska försvinna som egna discipliner och med tiden uppgå i något nytt. Skillnaden är helt avgörande. Den här tendensen, att oreflekterat använda i grunden ytterst problematiska begrepp i sina budskap, tycker jag man kan skönja överallt.

P120 and E-cadherin: Double-edged swords in tumor metastasis

Cell-cell adhesion by adherens junctions controls proliferation and cell polarization and is crucial to maintain epithelial architecture and homeostasis. Downregulation of two of the main components of adherens junctions, E-cadherin and p120, is an often recurring hallmark of carcinomas, causing loss of polarity and increased proliferation, survival and invasion of epithelial cells. On the other hand, tumor-promoting effects of both E-cadherin and p120 have been reported, substantiated by sustained, or even elevated expression of these molecules in many cancers. In this review, we will discuss how expression regulation by EMT, E-cadherin cleavage or p120 isoform expression can contribute to either tumor-supressing or tumor-promoting processes. Furthermore, we will focus on the contradictory functions of E-cadherin and p120 in the different phases of tumor progression, from carcinoma in situ up to the formation of distant metastasis. Finally, we will discuss the possibilities and challenges when using either protein as a biomarker

L1 Cell Adhesion Molecule in Cancer, a Systematic Review on Domain-Specific Functions

Contains fulltext : 208660.pdf (publisher's version ) (Open Access)L1 cell adhesion molecule (L1CAM) is a glycoprotein involved in cancer development and is associated with metastases and poor prognosis. Cellular processing of L1CAM results in expression of either full-length or cleaved forms of the protein. The different forms of L1CAM may localize at the plasma membrane as a transmembrane protein, or in the intra- or extracellular environment as cleaved or exosomal forms. Here, we systematically analyze available literature that directly relates to L1CAM domains and associated signaling pathways in cancer. Specifically, we chart its domain-specific functions in relation to cancer progression, and outline pre-clinical assays used to assess L1CAM. It is found that full-length L1CAM has both intracellular and extracellular targets, including interactions with integrins, and linkage with ezrin. Cellular processing leading to proteolytic cleavage and/or exosome formation results in extracellular soluble forms of L1CAM that may act through similar mechanisms as compared to full-length L1CAM, such as integrin-dependent signals, but also through distinct mechanisms. We provide an algorithm to guide a step-wise analysis on L1CAM in clinical samples, to promote interpretation of domain-specific expression. This systematic review infers that L1CAM has an important role in cancer progression that can be attributed to domain-specific forms. Most studies focus on the full-length plasma membrane L1CAM, yet knowledge on the domain-specific forms is a prerequisite for selective targeting treatment

Pak1 regulates the orientation of apical polarization and lumen formation by distinct pathways.

Contains fulltext : 108957.pdf (publisher's version ) (Open Access)The development of the basic architecture of branching tubules enclosing a central lumen that characterizes most epithelial organs crucially depends on the apico-basolateral polarization of epithelial cells. Signals from the extracellular matrix control the orientation of the apical surface, so that it faces the lumen interior, opposite to cell-matrix adhesion sites. This orientation of the apical surface is thought to be intrinsically linked to the formation of single lumens. We previously demonstrated in three-dimensional cyst cultures of Madin-Darby canine kidney (MDCK) cells that signaling by beta1 integrins regulates the orientation of the apical surface, via a mechanism that depends on the activity of the small GTPase Rac1. Here, we investigated whether the Rac1 effector Pak1 is a downstream effector in this pathway. Expression of constitutive active Pak1 phenocopies the effect of beta1 integrin inhibition in that it misorients the apical surface and induces a multilumen phenotype. The misorientation of apical surfaces depends on the interaction of active Pak1 with PIX proteins and is linked to defects in basement membrane assembly. In contrast, the multilumen phenotype was independent of PIX and the basement membrane. Therefore, Pak1 likely regulates apical polarization and lumen formation by two distinct pathways

Tunable Hybrid Matrices Drive Epithelial Morphogenesis and YAP Translocation

Contains fulltext : 229966.pdf (publisher's version ) (Open Access

Actin Filaments and Microtubules are Involved in Different Membrane Traffic Pathways That Transport Sphingolipids to the Apical Surface of Polarized HepG2 Cells

In polarized HepG2 hepatoma cells, sphingolipids are transported to the apical, bile canalicular membrane by two different transport routes, as revealed with fluorescently tagged sphingolipid analogs. One route involves direct, transcytosis-independent transport of Golgi-derived glucosylceramide and sphingomyelin, whereas the other involves basolateral to apical transcytosis of both sphingolipids. We show that these distinct routes display a different sensitivity toward nocodazole and cytochalasin D, implying a specific transport dependence on either microtubules or actin filaments, respectively. Thus, nocodazole strongly inhibited the direct route, whereas sphingolipid transport by transcytosis was hardly affected. Moreover, nocodazole blocked “hyperpolarization,” i.e., the enlargement of the apical membrane surface, which is induced by treating cells with dibutyryl-cAMP. By contrast, the transcytotic route but not the direct route was inhibited by cytochalasin D. The actin-dependent step during transcytotic lipid transport probably occurs at an early endocytic event at the basolateral plasma membrane, because total lipid uptake and fluid phase endocytosis of horseradish peroxidase from this membrane were inhibited by cytochalasin D as well. In summary, the results show that the two sphingolipid transport pathways to the apical membrane must have a different requirement for cytoskeletal elements