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Contribution of Extracellular Matrix to EMT Interactive Signaling Pathway

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Pathway Description:

One of the hallmark features of EMT is the loss of epithelial integrity, which results from the degradation of the adherens junctions that maintain epithelial cell-cell contact. A primary driver of this degradation is proteolytic digestion by matrix metalloproteinases (MMPs), the expression of which is regulated by EMT-associated signaling pathways (e.g., TGF-β). The degradation of adherens junctions is further promoted by the transcriptional repression of genes encoding epithelial-specific proteins (e.g., E-Cadherin, Occludins, Desmoplakins) by pro-EMT transcription factors such as SNAIL. During EMT, selected components of epithelial adherens junctions are replaced by proteins (e.g., N-Cadherin) that provide greater junctional flexibility, enabling cell detachment and enhanced cell motility. The process of EMT also involves remodeling of the action cytoskeleton, which is driven in part by altered expression of Ezrin/Radixin/Moesin (ERM) proteins such as Moesin, as observed in invasive breast cancer cells. ERM proteins also interact with CD44, a cell surface glycoprotein abundantly expressed in some cancer stem cells, and strongly associated with cell motility and cancer metastasis, in part through its function as a receptor for extracellular proteoglycans such as hyaluronan and versican.

The EMT transcription factor Twist has been reported to induce the formation of actin-rich membrane protrusions known as invadopodia, which recruit the proteases MMP-7, MMP-9 and MMP-14 to the leading edge where they degrade ECM and basement membranes, facilitating tumor invasion and metastasis. During EMT, other EMT-associated transcription factors such as Twist, Slug, Snail and Zeb have been shown to upregulate the expression of several epithelial extracellular matrix (ECM) proteins, including collagen 1, vitronectin and fibronectin. The expression of several integrin complexes are also upregulated during EMT, including α5β1, which binds fibronectin, and the integrins α1β1 & α2β1, which interact with collagen I and have been shown to mediate the disruption of E-cadherin complexes. Cellular interactions with the ECM have been shown to be modulated by ECM-associated proteins such as SPARC, a glycoprotein which promotes the interaction of collagen and α2β1. SPARC induces EMT by modulating the expression of SLUG and in melanoma and has been shown to be associated with increased aggressiveness. SERPINE1 (PAI-1), another epithelial ECM component, inhibits the binding of vitronectin to the integrin αvβ3. High serpin levels have been associated with aggressiveness in various cancer types; this has been suggested to result from Serpin-mediated disruption of the points of contact between cells and the ECM. TIMP1, in conjunction with CD63 has been shown to mediate an EMT-like transformational of normal cells through enhancement of β1 integrin signaling activity.

Selected Reviews:

We would like to thank Dr. Dimiter Avtanski, Director, Endocrine Research Laboratory, Friedman Diabetes Institute at Lenox Hill Hospital, Northwell Health, for reviewing this diagram.

created October 2018
  • KinaseKinase
  • PosphatasePosphatase
  • Transcription FactorTranscription Factor
  • CaspaseCaspase
  • ReceptorReceptor
  • EnzymeEnzyme
  • pro-apoptoticpro-apoptotic
  • pro-survivalpro-survival
  • GAP/GEFGAP/GEF
  • GTPaseGTPase
  • G-proteinG-protein
  • AcetylaseAcetylase
  • DeacetylaseDeacetylase
  • Ribosomal subunitRibosomal subunit
  • Direct Stimulatory ModificationDirect Stimulatory Modification
  • Direct Inhibitory ModificationDirect Inhibitory Modification
  • Multistep Stimulatory ModificationMultistep Stimulatory Modification
  • Multistep Inhibitory ModificationMultistep Inhibitory Modification
  • Tentative Stimulatory ModificationTentative Stimulatory Modification
  • Tentative Inhibitory ModificationTentative Inhibitory Modification
  • Separation of Subunits or Cleavage ProductsSeparation of Subunits or Cleavage Products
  • Joining of SubunitsJoining of Subunits
  • TranslocationTranslocation
  • Transcriptional Stimulatory ModificationTranscriptional Stimulatory Modification
  • Transcriptional Inhibitory ModificationTranscriptional Inhibitory Modification