title: Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling.
abstract: Cancer cells can invade in three-dimensional collagen as single cells or as a cohesive group of cells that require coordination of cell-cell junctions and the actin cytoskeleton. To examine the role of Gα13, a G12 family heterotrimeric G protein, in regulating cellular invasion in three-dimensional collagen, we established a novel method to track cell invasion by membrane type 1 matrix metalloproteinase-expressing cancer cells. We show that knockdown of Gα13 decreased membrane type 1 matrix metalloproteinase-driven proteolytic invasion in three-dimensional collagen and enhanced E-cadherin-mediated cell-cell adhesion. E-cadherin knockdown reversed Gα13 siRNA-induced cell-cell adhesion but failed to reverse the effect of Gα13 siRNA on proteolytic invasion. Instead, concurrent knockdown of E-cadherin and Gα13 led to an increased number of single cells rather than groups of cells. Significantly, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes to cell-cell junctions, reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Knockdown of the polarity protein Par3, which can function downstream of DDR1, also reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Overall, we show that Gα13 and DDR1-Par3 differentially regulate cell-cell junctions and the actin cytoskeleton to mediate invasion in three-dimensional collagen.
authors.affiliation: From the Departments of Medicine and; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Ilinois 60611.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Chow
authors.affiliation: From the Departments of Medicine and; Jesse Brown Veterans Affairs Medical Center, and.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ebine
authors.affiliation: Surgery, Feinberg School of Medicine.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Knab
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Ilinois 60611; Jesse Brown Veterans Affairs Medical Center, and; Surgery, Feinberg School of Medicine.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: From the Departments of Medicine and; Jesse Brown Veterans Affairs Medical Center, and.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: From the Departments of Medicine and; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Ilinois 60611; Jesse Brown Veterans Affairs Medical Center, and. Electronic address: h-munshi@northwestern.edu.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D053511:Matrix Metalloproteinase 14; D044365:GTP-Binding Protein alpha Subunits, G12-G13
keywords: G protein; cell polarity; collagen; invasion; metalloprotease