DEFINITION
SMADs are proteins that modulate the activity of transforming growth factor beta and BMP ligands
Details of SMAD kinetics 2007
In general, signaling is initiated with ligand-induced oligomerization of serine/threonine receptor kinases and phosphorylation of the cytoplasmic signaling molecules
- Smad2 and Smad3 for the TGF-β/activin pathway
- Smad1/5/8 for the Bone Morphogenetic Protein (BMP) pathway.
TGF_beta and BMP full pathway
Carboxy-terminal phosphorylation of Smads by activated receptors results in their partnering with the common signaling transducer Smad4, and translocation to the nucleus.
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)
TGF beta downstream
SMAD4 means
- alanine
high pyruvate, low mitochondrial respiration
- Glu/Gln < 1 hypoxia
- methionine and leucine high protein synthesis (mTOR mediated)
- Phe/Tyr > 1 high glucose and BH4
- Gly/Ser a< 1 and Serine easy methylations
- proline less NADPH and glutamine for DNA synthesis
- Threonine is
pointing to a cell metabolism with low NADPH and ATP (no proliferation)
It belongs to Cancer suppressors??
BMP downstream
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
degradation
CELLULAR FUNCTIONS
cellular localization,
biological function
The canonical transforming growth factor (TGF)-β/Smad signaling pathway. Members of the TGF-β family of growth factors (TGF-βs, activins, nodals) interact sequentially with two membrane receptors. TGF binds first to the constitutively active type II receptor ® and then the ligand-recepor complex associates with type I TGF-R. TGF-IIR (TβIIR) phosphorylates TGF-IR (TβIR) on a cluster of serine threonine residues. Activated TGF-RI propogates the signal downstream by directly phosphorylating Smad2 and Smad3. These form heterodimeric or trimeric complexes with Smad 4 and translocate into the nucleus where, in combination with LEF-1/T cell factor (TCF) family transcription factors, they down-regulate E-cadherin genes and initiate epithelial-mesenchymal transition. Complexes of Smad7 and Smurf1 or Smurf2 promote ubiquination and degradation of activated receptors limiting the intensity and duration of signaling. P, phosphorylation sites; SARA, small anchor for receptor activity
BMP and SMADs
SMAD4 takes part to the action of both SMAD2,3 and SMAD1,5,8 complex
- Enzymes
- Cell signaling and Ligand transport
- Structural proteins
Targets
REGULATION
(A) The canonical Smad pathway. TGF-ß bound to the two receptor serine/threonine kinases (type II, light green; type I, blue) initiates signalling by trans-phosphorylation of the type I receptor juxtamembrane domain (red arrow). Signalling ensues with R-Smad phosphorylation (Smad with black dot), oligomerization of R-Smad with Smad4, nuclear translocation and formation of complexes between transcription factors (TF) and co-activators/co-repressors (co) on chromatin. This leads to positive or negative regulation of mRNA synthesis (grey arrow). (B) The inhibitory I-Smad, together with the E3 ligase Smurf, exit the nucleus in response to the incoming TGF-ß signal and bind the receptor complex, leading to shut-down of R-Smad phosphorylation and receptor downregulation.
DIAGNOSTIC USE
