DDR1/E-cadherin complex regulates the activation of DDR1 and cell spreading

Wang, Chau Zen; Yeh, Yi Chun; Tang, Ming Jer

doi:10.1152/ajpcell.00101.2009

Cited by 49 publications

(67 citation statements)

References 42 publications

(67 reference statements)

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“…Consistent with this finding, the proapoptosis gene BIK was down-regulated in all samples. In addition, genes with a Zeb1 binding site present in their promoters were enriched in the set of genes down-regulated by EMT, including the gene discoidin domain receptor 1 (DDR1), which encodes an RTK involved in E-cadherin localization and distinguishes basal A from basal B cell lines (42)(43)(44)(45), and the gene follistatin (FST), which is a TGF-β antagonist (Tables S2 and S3) (46)(47)(48).…”

Section: Resultsmentioning

confidence: 99%

Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes

Taube¹,

Herschkowitz

Komurov

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

909

929

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The epithelial-to-mesenchymal transition (EMT) produces cancer cells that are invasive, migratory, and exhibit stem cell characteristics, hallmarks of cells that have the potential to generate metastases. Inducers of the EMT include several transcription factors (TFs), such as Goosecoid, Snail, and Twist, as well as the secreted TGF-β1. Each of these factors is capable, on its own, of inducing an EMT in the human mammary epithelial (HMLE) cell line. However, the interactions between these regulators are poorly understood. Overexpression of each of the above EMT inducers up-regulates a subset of other EMT-inducing TFs, with Twist, Zeb1, Zeb2, TGF-β1, and FOXC2 being commonly induced. Up-regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF-β1 signaling. Gene expression signatures (GESs) derived by overexpressing EMT-inducing TFs reveal that the Twist GES and Snail GES are the most similar, although the Goosecoid GES is the least similar to the others. An EMT core signature was derived from the changes in gene expression shared by up-regulation of Gsc, Snail, Twist, and TGF-β1 and by down-regulation of E-cadherin, loss of which can also trigger an EMT in certain cell types. The EMT core signature associates closely with the claudin-low and metaplastic breast cancer subtypes and correlates negatively with pathological complete response. Additionally, the expression level of FOXC1, another EMT inducer, correlates strongly with poor survival of breast cancer patients.

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Section: Resultsmentioning

confidence: 99%

Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes

Taube¹,

Herschkowitz

Komurov

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

909

929

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“…The kinetic profile of DDR phosphorylation is reminiscent of delayed negative feedback mechanisms commonly elicited to down-regulate immediate-early RTK activation (52). It has previously been reported that DDR1 serves to counteract the signaling effects of the ␣2␤1 integrin by reducing the activation of STAT1/3 (signal transducers and activators of transcription 1/3) and Cdc42 (53,54). Because ␣2␤1 integrin activation and formation of focal adhesion signaling complexes occur within minutes of collagen binding, it is plausible that DDRs have evolved as a late-wave negative feedback mechanism for the down-regulation of integrin signaling.…”

Section: Ddr Regulationmentioning

confidence: 99%

Discoidin Domain Receptors: Unique Receptor Tyrosine Kinases in Collagen-mediated Signaling

Valiathan

Arkwright

et al. 2013

Journal of Biological Chemistry

188

173

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The discoidin domain receptors (DDRs) are receptor tyrosine kinases that recognize collagens as their ligands. DDRs display unique structural features and distinctive activation kinetics, which set them apart from other members of the kinase superfamily. DDRs regulate cell-collagen interactions in normal and pathological conditions and thus are emerging as major sensors of collagen matrices and potential novel therapeutic targets. New structural and biological information has shed light on the molecular mechanisms that regulate DDR signaling, turnover, and function. This minireview provides an overview of these areas of DDR research with the goal of fostering further investigation of these intriguing and unique receptors. The discoidin domain receptor (DDR)2 family comprises two distinct members, DDR1 and DDR2, which were initially discovered in the early 1990s and characterized as receptor tyrosine kinases (RTKs) based on the presence of a catalytic kinase domain (KD) (1-7). Subsequently, collagens were identified as ligands for DDRs (8), thus establishing the unique characteristic of these receptors among other members of the RTK superfamily. Upon collagen binding, DDRs undergo tyrosine autophosphorylation with distinctive activation kinetics, which elicits genetic and cellular programs that regulate a variety of cell-collagen interactions. Despite their unique characteristics, the biochemical and cellular mechanisms by which DDRs mediate their multiple biological effects remain poorly defined. This minireview provides an overview of current information on DDR structure, regulation, and signaling. For information on specific DDR biological functions in processes such as cell adhesion, migration, and invasion over collagen matrices and their role in normal and pathological processes, the reader is directed to the following recent reviews (9 -11) DDR StructureThe DDR1 subfamily is composed of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. The five DDR1 isoforms are generated by alternative splicing. DDR1a, DDR1b, and DDR1c are full-length functional receptors, and DDR1d and DDR1e are truncated or kinase-inactive receptors (10, 12). Two additional secreted splice variants of DDR1 have also been identified (13). DDR1b and DDR1c contain an additional 37 residues within the intracellular juxtamembrane (IJXM) region. With the exception of the two secreted DDR1 isoforms, all DDRs are single-pass type I transmembrane glycoproteins that are characterized by the presence of six distinct protein domains: a discoidin (DS) domain, a DS-like domain, an extracellular juxtamembrane (EJXM) region, a transmembrane (TM) segment, a long IJXM region, and an intracellular KD (Fig. 1A). The presence of the N-terminal DS and DS-like domains is the defining feature of the DDR RTK subfamily. The DS domain exhibits high homology to a protein module originally identified in proteins from Dictyostelium discoideum (14). In this organism, the DS domain functions as a galactose-binding lectin, whic...

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“…Because collective migration requires cells to maintain intact cell-cell junctions, proteins such as E-cadherin maintain the integrity of cell-cell junctions. The collagen-binding protein discoidin domain receptor 1 (DDR1) has been shown to localize to cell-cell junctions and mediate cell-cell adhesion (10,11). In addition to regulating E-cadherin stability at the cell surface (12,13), DDR1, through its interaction with the Par3 polarity complex, can also regulate actin cytoskeleton dynamics (11).…”

Section: Pancreatic Ductal Adenocarcinoma (Pdac)mentioning

confidence: 99%

Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling

Chow

Ebine

Knab³

et al. 2016

Journal of Biological Chemistry

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Background:The role of G␣ 13 in mediating invasion in three-dimensional collagen is not well known. Results: G␣ 13 promotes invasion in three-dimensional collagen by disrupting cell-cell adhesion, whereas DDR1-Par3 signaling counteracts the effects of G␣ 13 by enhancing cell-cell adhesion. Conclusion: G␣ 13 and DDR1-Par3 differentially regulate cell-cell junctions to mediate three-dimensional invasion. Significance: Better understanding of how cells invade in three-dimensional collagen may identify potential therapeutic targets.

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DDR1/E-cadherin complex regulates the activation of DDR1 and cell spreading

Cited by 49 publications

References 42 publications

Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes

Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes

Discoidin Domain Receptors: Unique Receptor Tyrosine Kinases in Collagen-mediated Signaling

Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling

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