Length of TGFBR2 gene is 87641 bases. TGFBR2 gene encodes 8 exons. Orientation: plus strand.

The TGFBR2 gene encodes two well-known protein coding transcripts:
- TGFBR2-001(Ensembl version ENST00000295754.5): Encoded by 7 exons; mRNA length: 4621 bps; Translation length: 567 amino acid residues;
- TGFBR2-002(Ensembl version ENST00000359013.4): Encoded by 8 exons; mRNA length: 4605 bps; Translation length: 592 amino acid residues.

The TGFBR2 gene encodes two proteins through alternative splicing (592 aa and 567 aa long respectively); both can convey TGFβ signals. TGFBR2 is a transmembrane Serine/Threonine kinase. It has a molecular weight of 70/80kD. TGFBR2 consist of an N-terminal extra-cellular ligand binding ectodomain, a transmembrane region, and a C-terminal serine/threonine kinase domain. The ectodomain is formed by nine beta-strands and a single helix stabilised by a network of six intra strand disulphide bonds (Hart et al., 2002).

This protein is ubiquitously expressed in all cell types. Loss of TGFBR2 expression is linked with many pathological conditions involving cancer. The level of expression may vary depending up on cell-type.

Primarily, it is a transmembrane protein, involved in extra-cellular TGFβ ligand binding. However, ligand binding can trigger internalization of both ligand and receptors. Receptors internalized in endosomes can either be targeted to lysosomes for degradation or be recycled back to the cell surface for re-use (Chen et al., 2009).

TGFBR2 is an important member of the Transforming Growth Factor Beta (TGFβ) signaling pathway. The TGFβ signaling controls important cellular activities like cytostasis, apoptosis, epithelial to mesenchymal transition (EMT), migration, etc. in a context dependent manner (Massague et al., 2005; Feng and Derynck, 2005). These pleiotropic cytokines are encoded by 42 open reading frames in human. They are divided into two subfamilies, the TGFβ/Activin/Nodal subfamily and the BMP(bone morphogenetic protein)/GDF(growth and differentiation factor)/MIS(Muellerian inhibiting substance) subfamily, as defined by sequence similarity and the specific signaling pathways that they activate (Shi and Massague, 2003). These cytokines are known to convey cellular signals through the serine/threonine kinase family receptors - 7 type I and 5 type II receptors - that are dedicated to TGFβ signaling (Manning et al., 2002). TGFBR2 is the most important and well-characterized type II receptor of TGFβ family.
The TGFβ-SMAD signaling cascade gets activated when TGFβ ligand binds to the TGFBR2 (Massague, 1998; Shi and Massague, 2003). The TGFβ ligand is secreted as latent complex in which the TGFβ dimer is bound to the latency-associated peptide (LAP) (Young and Murphy-Ullrich, 2004). Many latent TGFβ binding proteins (LTBPs) can bind to and sequester this latent complex to extra cellular matrix (ECM) (Derynck et al., 2001). The latent TGFβ is activated by plasmins and MMP2 and MMP9 through proteolytic processing that leads to removal of LAP. The active form of TGF-β is a 25 KDa disulphide linked homodimer. (Derynck et al., 2001; Padua and Massague, 2009). TGFBR2 is a constitutively active kinase that occurs as homodimer (Hart et al., 2002; Shi and Massague, 2003). On ligand binding mediated activation, TGFBR2 forms heteromeric complex with type I TGFβ receptor (TGFBR1) (Luo and Lodish, 1997). TGFBR2 kinase mediated phosphorylation of Glycine/Serine-rich GS domain of TGFBR1 leads to activation of type I receptor kinase. Activated TGFBR1 then phosphorylates downstream SMAD transcription factors.
The pathway restricted SMADs-SMAD2 and SMAD3- are involved in signaling through TGFBR2/TGFBR1 receptor complexes. They are commonly called receptor regulated SMADs or R-SMADs. They bind directly to TGFBR1 and are phosphorylated at a C-terminal SSXS motif, that is exclusive and conserved for R-SMADs (Feng and Derynck, 2005; Schmierer and Hill, 2007). SMAD4 lacks a C-terminal SSXS motif and does not interact directly with TGFBR1. SMAD4 is commonly referred to as co-SMAD and serves as a common partner for all R-SMADs (Shi and Massague, 2003).
The binding of the R-SMAD to the type I receptor is mediated by adaptor proteins like SARA (SMAD anchor for receptor activation), a zinc double finger FYVE domain containing protein. They restrict SMAD2/3 proteins to the plasma membrane and early endosomes and thus facilitate the interaction of SMAD2/3 proteins with activated TGFBR1 (Panopoulou et al., 2002; Chen, 2009). The phosphorylated R-SMADs can form heteromeric complex with the common mediator SMAD (Co-SMAD, SMAD4) and this enables the nuclear translocation of the complex (Wrighton et al., 2009). In the nucleus, the SMAD transcription factors orchestrate the expression of various target genes; depending on the DNA binding partners they associate (Massague, 2008). The DNA binding partners are responsible for the context dependency exhibited by TGFβ signaling (Inman, 2005). Many protein phosphatases are responsible for switching off TGFβ signaling through R-SMAD dephosphorylation and dictate the strength and duration of TGFβ signaling (Wrighton et al., 2009). The inhibitory SMADs (SMAD 6 and SMAD 7) are responsible for feedback repression of this signaling pathway (Xu, 2006). SMAD7 acts through competition for receptor mediated phosphorylation, and through the recruitment of SMAD ubiquitination regulatory Factors1 or 2 (Smurf1/Smurf2) to R- SMADs (Lönn et al., 2009).
In addition to the canonical signaling through the SMADs, TGFBR2 can activate many non-SMAD pathways like PI3K-Akt, JNK, p38MAPK, ROCK, PKC, PP2A, Ras, Erk1/Erk2 and Rho-like GTPases including RhoA, Rac and Cdc42 (Zhang, 2009). These non-SMAD signaling pathways add greatly towards the context-dependent nature of TGFβ signaling.
Many studies consider TGFβ alterations as a key reason for tumorigenesis (Derynck et al., 2001; Seoane, 2006). These alterations arise at genetic as well as at epigenetic level. While mutations are responsible for major share of genomic level TGFβ aberrations, the microRNA alterations contribute towards a fair share of the epigenetic alterations (Sivadas and Kannan, 2013). Besides, loss of integration of TGFβ signaling with other important pathways such as p53 signaling is an important reason for tumorigenesis (Massague, 2008).

The TGFBR2 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken and zebra fish. Notably, TGFBR2 of human beings and chimpanzee shows 100% and 99.6% identity, at protein and DNA level respectively. Furthermore, 72 organisms have orthologs with human gene TGFBR2.

Somatic mutations of TGFBR2 is a common event in various cancers (Seoane, 2006), Loeys-Dietz syndrome, Marfan syndrome, etc. (Loeys et al., 2006; Singh et al., 2006; Stheneur et al., 2008). Deletion of the chromosomal region 3p, that carries TGFBR2 is reported in many solid tumors (Kok et al., 1997).