R-SMAD stands for receptor-regulated SMAD. Smads are transcription factors that transduce extracellular TGF-ß superfamily ligand signaling from cell membrane bound TGF-ß receptors into the nucleus where they activate transcription TGF-ß target genes. R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-ß receptors through their intracellular kinase domain, leading to r-SMAD activation. R-SMADS include SMAD2 and SMAD3 from the TGF-ß/Activin/Nodal branch, and SMAD1, SMAD5 and SMAD8 from the BMP/GDP branch of TGF-ß signaling .

R-Smads include SMAD1

Mothers against decapentaplegic homolog 1

Mothers against decapentaplegic homolog 1 also known as SMAD family member 1 or SMAD1 is a protein that in humans is encoded by the SMAD1 gene.-Nomenclature:...

, SMAD2

Mothers against decapentaplegic homolog 2

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' and the C....

, SMAD3

Mothers against decapentaplegic homolog 3

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins.The human SMAD3 gene is located on chromosome 15...

, SMAD5

Mothers against decapentaplegic homolog 5

Mothers against decapentaplegic homolog 5 also known as SMAD5 is a protein that in humans is encoded by the SAMD5 gene.SMAD5, as its name describes, is a homolog of the Drosophila gene: "Mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGFβ...

, and SMAD8.

In response to signals by the TGF-β superfamily of ligands

Ligand

In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 these proteins associate with receptor kinase

Kinase

In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...

s and are phosphorylated at an SSXS motif at their extreme C-terminus. These proteins then typically bind to the common mediator Smad or co-SMAD SMAD4

Mothers against decapentaplegic homolog 4

SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily...

.

Smad complexes then accumulate in the cell nucleus

Cell nucleus

In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

 where they regulate transcription of specific target genes:

• SMAD2 and SMAD3 are activated in response to TGF-β/Activin or Nodal signals.
• SMAD1, SMAD5 and SMAD8 are activated in response to BMPs bone morphogenetic protein
  Bone morphogenetic protein
  Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
  
  or GDP signals.

SMAD6 and SMAD7 may be referred to as I-SMADs (inhibitory SMADS), which form trimers with r-SMADS and block their ability to induce gene transcription by competing with r-SMADs for receptor binding and by marking TGF-ß receptors for degradation.

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