Epithelial Cells Cell Polarity TGF-b-Induced EMT

MUC-1 O-glycosylation Epithelial Cells ZO-1 Occludin Apical Membrane Tight F-Actin Microvilli Junction Claudin F-Actin p120 β-Catenin Adherens F-Actin Ezrin TGF-β dimer Junction E-Cadherin α-Catenin Plakophilin Crumbs Complex PAR Complex Desmocollin Desmoplakin Desmosome PtdIns(4,5)P2 TGF-β RII TGF-β RI CRB Cdc42Par6 Desmoglein Cytokeratin Pals1 PatJ Tight Junction Plakoglobin aPKC Par3 Domain Smad7 Extracellular PTEN JNK ERK1/2 p38 SARA Smurf1 Cortical Actin Cytoskeleton Space Par3 ZO-1 Adherens Junction PI 3-K Domain Smad-independent Signaling (–) Smad7 Translocation Smad2/3

PtdIns(3,4,5)P3 Smad4 Smad4 NEDD4 Cytokeratin Intermediate Filaments Smad2 Smad4 Smad3 LLGL Proteasome SCRIB DLG Scribble Complex Fibronectin Twist Smad2/3 Vitronectin ZEB 1/2 Microtubule Network Smad4 N-Cadherin Snail Basolateral Membrane CoA, Collagen I Slug CoR MMPs

DNA-binding (+) Claudin Desmoplakin Transcription Factor Occludin Cytokeratins E-Cadherin Plakoglobin Integrins β α Nidogen-1/Entactin Perlecan Laminin Collagen IV Transcriptional Repression Cell-Cell Adhesion Disassembly Actin Reorganization of E-Cadherin

TGF-β dimer EGF TGF-β RII TGF-β RI IGF FGF Receptor TNF-α Tyrosine Kinase Par6 TNF RI

Apical Focal Adhesion Constriction Actin Depolymerization F-Actin Smurf1 Occludin Wnt Frizzled Myosin II Ras RhoA α-Actinin Myosin II ROCK AxinCK1 Dishevelled GSK-3 PI 3-K Src Zyxin MLC Phosphatase APC Proteasome FAK Vinculin RhoA ILK Talin (Inactive) Hakai Talin FAK F-Actin E-Cadherin LIMK Akt Paxillin FAK Stress Fiber Formation NICD Talin MEK1/2 Proteolytic Processing E-Cadherin Clathrin Caveolin-1 Ectodomain Shedding αβ Integrins NFκB GSK-3β Notch MMP-3, -9 Plasma Membrane Co lin β-Catenin (Inactive) ADAM10 (Inactive)  Stabilization Actin Depolymerization MMP-3, -9 DSL Nicastrin Endocytosis γ-Secretase APH1A Rac1b Snail ERK1/2 Nicastrin PSENEN Budding Accumulation Presenilin-1 Clathrin-coated APH1APSENEN γ-Secretase Dynamin Vesicle Presenilin-1 NM23-H1 GTP-Dynamin Zyxin ROS Twist1 β-Catenin GDP-Dynamin CSL Slug TCF/LEF Snail Vesicle ROS Fission Lysosome HIF-1α β-Catenin Stabilization Twist, ZEB1 HIF-1αTCF/LEFNFκB RBBP4 Actin Stress Fibers SUZ12 Rap1 EZH2 Twist ZEB1 E-Cadherin Snail Integrin-based Focal Adhesion

Mesenchymal Cells Matrix Remodeling & Cell Migration Mesenchymal to Epithelial Transition

γδ T Cell BMP-7 dimer Type II R Activin RIA

Smad8 FGF R2 (IIIb) Stromal Cells (Epithelial) N-Cadherin FGF R2 (IIIb) Smad5 PSLG-1 FGF-10 (Epithelial) Smad1 FGF-7 Smad4 Versican RAS (+) MEK1/2 F-Actin N-Cadherin (α-Smooth Muscle Actin) (+) Immune Cell ERK1/2 Recruitment FGF R2 (IIIc) p120 Smad4 Smad1/5/8 Isoform Switch (Mesenchymal) Epithelial CoA, Morphogenesis E-Cadherin via CoR ID2 Alternative EGF R EGF dimer Splicing Slug DNA-binding N-Cadherin PDGF R Snail PDGF R MMPs Transcription Factor Twist Fox2 PDGF dimer PDGF dimer Src Twist1 PDGF R FGF R2 mRNA

Rac Src (–) Microtubule Organizing Developing Center Cytokeratin Developing Intermediate Adherens Cortactin (–) Filaments Junction Recruitment Vimentin (+) Intermediate Src ADAM12,15,19 MMP-9 Filaments Cortactin AFAP MMP-2 MMP-9 SHC1 TSK4 MT1-MMP DDR2 TIMP-2 MMP-2 β Pro-MMP-2 β Integrin 3 Integrins 1,3 α Collagen I α v Fibronectin v MMP-2 (Active) Plectin Laminin-5 Hyaluronan Vitronectin FAP dimer WASP Plasmin ARP2/3 uPA Pro-MMP-2 uPAR Epithelial to Mesenchymal Transition Epithelial to mesenchymal transition (EMT) is a biological process by which differentiated epithelial cells lose epithelial characteristics and acquire a EMT is a transient and reversible process that can be classified into three subtypes, depending on the biological and functional setting in which it occurs: migratory, mesenchymal phenotype. Although the intermediate stages of EMT have been challenging to capture and describe, the initiation and Type 1: Development Type 2: Wound Healing/Fibrosis Type 3: Metastasis completion of EMT are better understood. Typically, epithelial cells display apical-basal polarity and adhere tightly to each other via tight and adherens EMT underlies the generation of secondary epithelia EMT generates fibroblasts in response to tissue injury EMT allows neoplastic cells to become motile and junctions near the apical membrane and desmosomes in the basolateral membrane. The morphological changes that occur during EMT are induced by during embryonic development and is essential for and inflammation and is important during wound invasive and leave the primary epithelial tumor site. A signal transduction pathways that reduce E-Cadherin expression, drive the disassembly of intercellular adhesion complexes, and promote Actin stress gastrulation, neural crest cell migration, and organ healing and tissue regeneration. Organ fibrosis is distal MET event promotes secondary tumor formation development. thought to occur, in part, due to continual EMT and cancer progression in other organs. fiber and focal adhesion formation. These types of cellular changes result in the phenotypic transition to an elongated, mesenchymal cell that expresses processes following the attenuation of inflammation. extracellular matrix remodeling enzymes and has an increased capacity for migration and invasion. EMT and the reverse process, mesenchymal to epithelial transition (MET), are thought to be controlled by local cues within distinct microenvironments. For example, one model suggests that intraepithelial γδ T cells, which secrete cytokines, chemokines, and growth factors, regulate EMT/MET pathways in certain contexts. Overall, increasing evidence indicates that immune cell-dependent EMT/MET influences epithelial carcinogenesis progressionin vivo.

Transition to EMT online at: www.RnDSystems.com/EMT

NOTE: This poster conveys a general overview and should be considered neither comprehensive nor definitive. The details of the process are understood to be subject to interpretation. © R&D Systems, Inc. 2013

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