Regulation of Smad activities

Abstract

TGF-beta (Transforming Growth Factor-beta) cytokines employ Smad proteins as the intracellular mediator of signaling. Upon TGF-beta stimulation, the cytoplasmic Smads become phosphorylated and consequently accumulate in the nucleus to regulate target gene expression. The cytoplasm-to-nucleus redistribution of Smads, as well as the ability of Smads to activate or repress gene transcription, is under multiple layers of regulation by factors not limited to TGF-beta. With recent advance in the knowledge of regulatory factors impinged on Smads, we are beginning to understand the complexity in cellular responses to TGF-beta.

Figure 1

Nucleoporins, transport receptors and retention factors regulate the nucleo-cytoplasmic distribution of R-Smads and Smad4. Note the involvement of importin β1 is limited to Smad3 only. The model suggests that Smad2 and Smad3 need to be dephosphorylated and dissociated from Smad4 before they can be exported to the cytoplasm by exportin 4 (for Smad2/3) and CRM-1 (for Smad4).

Figure 2

Relative positions of phosphorylated residues in R-Smads. The responsible kinases are indicated with color coding. Only phosphorylation sites verified by mutational analyses are highlighted. TβRI: type I TGF-β receptor; BMPRI: type I BMP receptor.

Figure 3

Positive and negative regulation of R-Smad functions. Factors that facilitate or inhibit R-Smads functions are categorized and shown in red and grey boxes, respectively.