BMPs constitute the largest part of the TGF-b superfamily. The members of the BMP family differ from other members of the TGF-b superfamily in having seven conserved cysteine residues in the polypeptide. The BMPs are synthesized as precursor proteins. The active BMP is released by proteolytic removal of the signal peptide and pro-peptide.
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BMP Full Form: Types of BMPs
Check below the list of BMPs and their functions.
It is a metalloprotease that is involved in cartilage development
It acts as a disulfide-linked homodimer and plays a key role in osteoblast differentiation
It induces bone formation
It regulates the development of teeth, limbs and bone. It also plays an important role in dorsal-ventral axis formation and ovarian follicle development
It helps in cartilage development
It plays an important role in controlling iron homeostasis by regulation of hepcidin
It induces the production of SMAD1 and also plays a key role in renal development and repair
It plays an important role in bone and cartilage development
It is expressed in the hippocampus area
It plays an important role in the development of the embryonic heart
It plays an important role in controlling the anterior-posterior patterning
It controls oocyte and follicular development
BMP Full Form: Functions of BMPs
- Play an important role in embryonic development specifically in early skeletal formation.
- The main function of BMPs are to allow the undifferentiated pluripotent cells to differentiate into cartilage and bone-forming cells.
- BMP signalling controls the early formation of the Mullerian duct, which eventually gives rise to the female reproductive tract.
- BMP signalling is also involved in the formation of foregut and hindgut, intestinal villus patterning and endocardial differentiation.
- BMPS are also involved in the process of adipogenesis, by functionally regulating the adipose tissue. The process of white adipogenesis is favoured by BMP4 while the process of brown adipogenesis is done by BMP7.
BMP Full Form: Mode of Signaling
- The members of the TGF-b family activate members of the Smad family of transcription factors.
- The TGF-b ligand binds to a type II TGF-b receptor, which allows that receptor to bind to a Type I TGF-b
- As the two receptors are in close contact, the Type II receptor phosphorylates a serine or threonine residue on the Type I receptor.
- This results in асtivаtiоn оf the Tyрe-I reсeрtоr.
- The activated Type- I receptor now phosphorylates the Smad proteins.
- There are three types of Smad proteins that function in the TGF-b signalling pathway:
- R-Smads (Receptor-regulated Smads) – Smad 2 and Smad 3
- Co-Smads – Smad 4
- I-Smads (Inhibitory Smads)- Smad 7
A. TGF-ß Proteins Are Stored in An Inactive Form in The Extracellular Matrix
- The TGF-b is synthesized with a long N-terminal prodomain that is cleaved off in the Golgi complex.
- The monomeric form of TGF-b contains three intramolecular disulfide linkages.
- This prodomain remains noncovalently attached to the TGF-b growth-factor domain as the protein is secreted and prevents binding of the TGF-b to its cell-surface receptors.
- Certain mechanisms like protease digestion release the TGF-b from the extracellular matrix which leads to activation of cell signalling.
B. Three Separate TGF-ß Receptor Proteins Participate in Binding TGF-ß and Activating Signal Transduction
- The three TGF-b receptor complexes were referred to as RI, RII and RIII respectively.
- The most abundant is the RIII, which is a b-glycan, which is a cell-surface proteoglycan.
- RIII is a transmembrane protein that binds and concentrates TGF-b molecules near the cell surface.
- The RI and RII receptors are dimeric transmembrane proteins with serine/threonine kinases as part of their cytosolic domains.
- RII exhibits constitutive kinase activity; that is; it is active even when not bound to TGF-b.
- The binding of TGF-b to RII generates a new molecular surface at the TGF-b-RII interface that docks to RI; which results in ligand-induced receptor hetero-oligomerization.
- An RII subunit then phosphorylates serine and threonine residues in a highly conserved sequence of the RI subunit adjacent to the cytosolic face of the plasma membrane, thereby activating the RI kinase activity.
C. Activated Tgf-ß receptors Phosphorylate Smad Transcription Factors
- In Some Cells, Tgf-B Binds to The Type Iii Tgf-B Receptor (riii), Which Presents the Tgf-B to The Type Ii Receptor
- In other cells, TGF-b binds directly to RII, a constitutively active kinase.
- Ligand-bound RII recruits and phosphorylates the type I TGF-b receptor
(RI), which does not directly bind TGF-b.
- The RI kinase activity inhibition gets released as a result.
- Асtivаted RI then рhоsрhоrylаtes Smаd2 оr Smаd3 setting in mоtiоn а соnfоrmаtiоnаl сhаnge thаt unveils its nuсleаr lосаlizаtiоn signаl (NLS).
- Two phosphorylated molecules of Smad 2/3 bind to a co-Smad (Smad4) molecule, which is not phosphorylated and to an importin; forming a large cytosolic complex.
- After the entire complex translocate into the nucleus; RAN-GTP causes dissociation of the importin
- A nuclear transcription factor (TFE3) then associates with the Smad 2/3/Smad4 complex forming an activation complex that binds to regulatory sequences of a target gene.
- The activation complex then recruits transcriptional co-activators and induces gene transcription.
- Smad 2/3 is dephosphorylated by a nuclear phosphatase and recycles through a nuclear pore to the cytosol; where it can be re-activated by another TGF-b receptor complex.
D. Negative Feedback Loop Regulates Tgf-SS/smad Signalling
- Two Cytosolic Proteins Sno N and Ski Are Induced by Tgf-B Signaling in Virtually All Body Cells.
- They down-regulate the TGF-b/Smad signaling pathway.
- Ski represses Smad function by directly binding to Smad4.
- Thus, binding of Ski disrupts the normal interactions between Smad3 and Smad4 necessary for transcriptional activation.
- Ski recruits the protein N-CoR which directly binds to mSin3A.
- mSin3A then interacts with histone deacetylase (HDAC).
- HDAC is an enzyme that promotes histone deacetylation on nearby promoters; thereby repressing gene expression.
- Thus, both the processes transcriptional activation induced by TGF-b and mediated by Smad complexes is shut down.
- Among the other proteins induced after TGF-b stimulation after the I-Smads, especially Smad7.
- Smad 7 blocks the ability of activated Type I TGF-b receptors (RI) to phosphorylate R-Smad proteins.
- Smad7 also targets TGF-b receptors for degradation.
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