To (TGF)beta or not to (TGF)beta: fine-tuning of Smad signaling via post-translational modifications

Abstract

Smad proteins are key signal transducers for the TGF-beta superfamily and are frequently inactivated in human cancers, yet the molecular basis of how their levels and activities are regulated remains unclear. Recent progress, discussed herein, illustrates the critical roles of Smad post-translational modifications in the cellular outcome to TGF-beta signaling.

Figure 1. Regulation of R-Smads by (de)phosphorylation

The type I receptor kinase phosphorylates the C-terminal distal SXS motif of R-Smads in response to ligand. This is the key step in initiating signal transduction. PPM1A has recently been identified as the serine/threonine phosphatase that dephosphorylates the phospho-SXS in Smad1/2/3, and SCPs 1, 2 and 3 as phosphatases that can dephosphorylate the phospho-SXS in Smad1 as well as the Smad1/2/3 linker. The exact localization of R-Smad linker phosphorylation by MAPK, and linker dephosphoryation by SCPs, is not known.

Figure 2. Known post-translational modifications of Smads

In the Smad2/3 box, amino acid residues are numbered in the Smad2/Smad3 order. All amino acid numbers are based on human sequences for Smad2 (NP_005892), Smad3 (NP_005893), Smad4 (NP_005350) and Smad7 (NP_005895). Note that the Smad3 sequence is incorrectly numbered in many publications. Smad2 exon 3, inserted between the NLS and DNA-binding domain is shown. Several other kinases such as CKIε and MEKK also phosphorylate R-Smads at unidentified sites. ERK also phosphorylates the linker region of BMP-activated Smad1 and perhaps Smad5/8. Smad4 contains a NES.