Transcription factors SMAD proteins

The phosphorylation state of the transcription factor NF-AT has a different effect on translocation. The phosphorylated form of this protein is localized in the cytosol and requires dephosphorylation by the protein phosphatase calcineiuln in order to be translocated to the nucleus (see also 7.5.2). Other examples for phosphorylation-dependent nuclear translocation include the STAT-proteins (see 11.1.3.2) and the SMAD-proteins (see 12.1.2). 

The R-Smad proteins interact with type I receptor and co-regulatory Smad (co-Smad) proteins in the signal cascade by virtue of conserved MH1 and MH2 domains at their N- and C-termini, which are separated by a variable, non-conserved region. These domains possess DNA binding and transcriptional activation functions, respectively. The inactive MH1 domain interacts with the MH2 domain in an auto-inhibitory manner. However, once C-terminal phosphorylation by the type I receptor occurs, this inhibitory association is alleviated and the R-Smad is then able to interact with its appropriate co-Smad. The phosphorylated R-Smad/co-Smad complex is capable of translocation to the cell nucleus where, in coordination with nuclear factors, it is able to exert its transcriptional activation function. 

Figure 3.4 Factors affecting foreign body reaction and potential points of intervention at the level of the myofibroblast (1) inhibit synthesis or release of TGF-P (2) block stimulation by TGF-P of its membrane receptors on the activated fibroblast (3) inhibit the Smad proteins, which transfer the TGF-P effect to the nucleus (4) inhibit transcription of procollagen mRNA (5) inhibit translation of the message to form procollagen (6) inhibit prolyl-4-hydroxylase, which creates hydroxyproline and facilitates helix formation (7) inhibit lysyl oxidase, which cross-links the collagen (8) enhance the function of MMPs, which degrade collagen, or inhibit TIMPs, which degrade MMPs.

SMADs are cytoplasmic proteins with molecular weights ranging firom 42 to 60 kDa. Pathw -restricted SMADs and common or Co-SMADs are distinguished. The pathway-restricted, or receptor-regulated SMADs (R-SMADs), are phosphorylated on serines in the MH2 domain by TGF-P receptor I. The phosphorylated, receptor-regulated SMADs associate with a constitutive, common Co-SMAD (SMAD 4), and the heterodimeric SMAD comploc is translocated to the nucleus where it binds either directly or with the help of other transcriptional factors to enhancers and promoters of specific gene elements (Fig. 6.4) (see also Chapter 9). 

The trans-regulatory factors that mediate the Bmp response are of obvious interest. Although smad proteins are well-known as transducers of the Bmp signal from cytoplasm to nucleus (von Bubnoff and Cho, 2001), they bind weakly to DNA and are thought to require sequence-specific transcription factors for their function. It will thus be informative to examine closely the Msx2 Bmp responsive cis-regulatory element and cognate factors. 

Researchers Identified the transcription factors downstream from TGFp receptors In Drosophila from genetic studies similar to those used to dissect receptor tyrosine kinase pathways (see Section 14.3). These transcription factors in Drosophila and the related vertebrate proteins are now called Smads. Three types of Smad proteins function in the TGFp signaling pathway receptor-regulated Smads (R-Smads), co-Smads, and Inhibitory or antagonistic Smads (TSmads). 

The frog TGF(3 family members called BMP2 and BMP4 have inductive effects similar to those of Dpp protein and indeed are the vertebrate proteins most closely related in sequence to Dpp. Most or all components of the TGF(3 signaling pathway, including Smad transcription factors, appear to be present and participating in development in all animals... 

For example, STAT proteins are transcription factors phosphorylated by JAK-STAT receptors, and SMAD proteins are transcription factors phosphorylated by serine-threonine kinase receptors such as the transforming growth factor-(3(TGF- 3) receptor (see Chapter 11). 

---