Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor.
Transforming growth factor-beta (TGF-beta) signaling proceeds from the cell membrane to the nucleus through the cooperation of the type I and II serine/threonine kinase receptors and their downstream SMAD effectors. Although various regulatory proteins affecting TGF-beta-mediated events have been described, relatively little is known about receptor interactions at the level of the plasma membrane. Caveolae are cholesterol-rich membrane microdomains that, along with their marker protein caveolin-1 (Cav-1), have been implicated in the compartmentalization and regulation of certain signaling events. Here, we demonstrate that specific components of the TGF-beta cascade are associated with caveolin-1 in caveolae and that Cav-1 interacts with the Type I TGF-beta receptor. Additionally, Cav-1 is able to suppress TGF-beta-mediated phosphorylation of Smad-2 and subsequent downstream events. We localize the Type I TGF-beta receptor interaction to the scaffolding domain of Cav-1 and show that it occurs in a physiologically relevant time frame, acting to rapidly dampen signaling initiated by the TGF-beta receptor complex.
Razani
B
B
Department of Molecular Pharmacology and The Albert Einstein Cancer Center and the Departments of Medicine and Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461.
Zhang
X L
XL
Bitzer
M
M
von Gersdorff
G
G
Böttinger
E P
EP
Lisanti
M P
MP
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D051242:Caveolin 1; D022461:Caveolins / Q000502:physiology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology*; D051899:Smad2 Protein; D022061:Tacrolimus Binding Protein 1A / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D022061:Tacrolimus Binding Protein 1A