title: Cdc42 regulates extracellular matrix remodeling in three dimensions.
abstract: Extracellular matrix (ECM) actively participates in normal cell regulation and in the process of tumor progression. The Rho GTPase Cdc42 has been shown to regulate cell-ECM interaction in conventional two-dimensional culture conditions by using dominant mutants of Cdc42 in immortalized cell lines that may introduce nonspecific effects. Here, we employ three-dimensional culture systems for conditional gene targeted primary mouse embryonic fibroblasts that better simulate the reciprocal and adaptive interactions between cells and surrounding matrix to define the role of Cdc42 signaling pathways in ECM organization. Cdc42 deficiency leads to a defect in global cell-matrix interactions reflected by a decrease in collagen gel contraction. The defect is associated with an altered cell-matrix interaction that is evident by morphologic changes and reduced focal adhesion complex formation. The matrix defect is also associated with a reduction in synthesis and activation of matrix metalloproteinase 9 (MMP9) and altered fibronectin deposition patterning. A Cdc42 mutant rescue experiment found that downstream of Cdc42, p21-activated kinase (PAK), but not Par6 or WASP, may be involved in regulating collagen gel contraction and fibronectin organization. Thus, in addition to the previously implicated roles in intracellular regulation of actin organization, proliferation, and vesicle trafficking, Cdc42 is essential in ECM remodeling in three dimensions.
authors: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors: Nisha S
authors: NS
authors: Sipes
authors: Yuxin
authors: Y
authors: Feng
authors: Fukun
authors: F
authors: Guo
authors: Hyung-Ok
authors: HO
authors: Lee
authors: Fu-Sheng
authors: FS
authors: Chou
authors: Jonathan
authors: J
authors: Cheng
authors: James
authors: J
authors: Mulloy
authors: Yi
authors: Y
authors: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005353:Fibronectins; C518597:Par6 protein, mouse; D054462:p21-Activated Kinases; D020780:Matrix Metalloproteinase 9; D020764:cdc42 GTP-Binding Protein