title: Smad7 is required for TGF-beta-induced activation of the small GTPase Cdc42.
abstract: Transforming growth factor beta (TGF-beta) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-beta receptors. The inhibitory Smads, Smad6 and Smad7, are considered to function as negative regulators of the TGF-beta/Smad signaling cascade. In a previous study, we found that TGF-beta induces rearrangements of the actin filament system in human prostate carcinoma cells and that this response requires the small GTPases Cdc42 and RhoA. On the basis of the current view on the function of Smad7 in TGF-beta signaling, we hypothesized that Smad7 would function as a negative regulator of the TGF-beta-induced activation of Cdc42 and RhoA, but instead we found that the reverse is the case; Smad7 is required for the TGF-beta-induced activation of Cdc42 and the concomitant reorganization of the actin filament system. These observations propose a novel role for Smad7 in TGF-beta-dependent activation of Rho GTPases.
authors.affiliation: Ludwig Institute for Cancer Research, Biomedical Center, Box 595, 751 24 Uppsala, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Edlund
authors.forename: Maréne
authors.initials: M
authors.lastname: Landström
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Pontus
authors.initials: P
authors.lastname: Aspenström
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D019256:Cadmium Chloride / Q000494:pharmacology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D051906:Smad7 Protein; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000819:agonists / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D019256:Cadmium Chloride; D002867:Chromones; D004268:DNA-Binding Proteins; D006160:Guanosine Triphosphate; D007093:Imidazoles; D020559:Monomeric GTP-Binding Proteins; D009025:Morpholines; D020319:Oligodeoxyribonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020764:cdc42 GTP-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases; C497806:SMAD7 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580