title: TGF-beta signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis.
abstract: The molecular mechanisms governing the cell behaviors underlying morphogenesis remain a major focus of research in both developmental biology and cancer biology. TGF-beta ligands control cell fate specification via Smad-mediated signaling. However, their ability to guide cellular morphogenesis in a variety of biological contexts is poorly understood. We report on the discovery of a novel TGF-beta signaling-mediated cellular morphogenesis occurring during vertebrate gastrulation. Activin/nodal members of the TGF-beta superfamily induce the expression of two genes regulating cell adhesion during gastrulation: Fibronectin Leucine-rich Repeat Transmembrane 3 (FLRT3), a type I transmembrane protein containing extracellular leucine-rich repeats, and the small GTPase Rnd1. FLRT3 and Rnd1 interact physically and modulate cell adhesion during embryogenesis by controlling cell surface levels of cadherin through a dynamin-dependent endocytosis pathway. Our model suggests that cell adhesion can be dynamically regulated by sequestering cadherin through internalization, and subsequent redeploying internalized cadherin to the cell surface as needed. As numerous studies have linked aberrant expression of small GTPases, adhesion molecules such as cadherins, and TGF-beta signaling to oncogenesis and metastasis, it is tempting to speculate that this FLRT3/Rnd1/cadherin pathway might also control cell behavior and morphogenesis in adult tissue homeostasis.
authors.affiliation: Department of Developmental and Cell Biology, Developmental Biology Center, University of California at Irvine, Irvine, California 92697, USA.
authors.forename: Souichi
authors.initials: S
authors.lastname: Ogata
authors.forename: Junji
authors.initials: J
authors.lastname: Morokuma
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Hayata
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kolle
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.forename: Naoto
authors.initials: N
authors.lastname: Ueno
authors.forename: Ken W Y
authors.initials: KW
authors.lastname: Cho
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D018076:DNA, Complementary / Q000235:genetics; D004705:Endocytosis; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009024:Morphogenesis; D009154:Mutation; D055457:Nodal Protein; D010641:Phenotype; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D018076:DNA, Complementary; C542073:FLRT3 protein, Xenopus; D008565:Membrane Proteins; D055457:Nodal Protein; D017468:Receptors, Fibroblast Growth Factor; C491770:Rnd1 protein, Xenopus; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D028341:Activins; D020741:rho GTP-Binding Proteins