Signalling & Genetics of Craniofacial Disorders Flashcards
Bone morphogenic proteins (BMP) when applied to bone defects would:
- promote osteoblast differentiation
- accelerate bone healing
Which bone morphogenic proteins (BMP) are FDA approved?
BMP-2 and BMP-7
BMP is a subfamily of which superfamily?
Transforming growth factor (TGF)-beta
TGF-beta superfamily has which subfamilies?
TGF-beta, activin, and BMP
What is similar between subfamilies of (TGF)-beta?
Structurally similar and therefore signal transduction pathway is similar
Growth factors like BMP are found where?
In small portion by weight («10%) in bone
Signal transduction requires:
- protein-protein interaction (direct binding)
- post translational modification (like phosphorylation, etc)
- usually needs growth factor-receptor-signal transducer-transcription factor (ie. there are 4 important players in signal transduction)
Where do growth factors bind?
membrane bound proteins (bind with very high affinity)
Binding of growth factors leads to:
cascade of intracellular secondary messages, and then modulation of other proteins or enhanced transcription of specific genes
growth factor receptors consist of which peptide domains?
extracellular, transmembrane and intracellular
2 types of kinase receptors
tyrosine kinase receptor and serene/threonine kinase receptor (because these amino acids can be phosphorylated)
Activation of TGF-beta/BMP signalling
- two types of receptors (I and II)
- growth factor dimerize and bind to type II causes conformational change
- type I receptor recruited and forms complex with type II-growth factor
- SMAD complex recruited to activated receptor complex, phosphorylation occurs
- SMAD then acts as transcription factor
What is SMAD?
A signal transducer
What is a signal transducer?
molecules/proteins that are utilized for intracellular signalling (membrane to nucleus)
5 examples of signal transducers and what type of signalling they’re involved in
Smad in TGF/BMP signalling MAPK in MAP kinase signalling JAK/STAT is JAK/STAT signalling IKK in NF-kB signalling GSK and beta-catenin in Wnt signalling
**probably more information than needed
growth factors activity controlled at multiple steps by
- inhibition by pro domain
- inhibition by ECM binding protein
- inhibition by ECM antagonists
- stored within ECM
Growth factor examples in TGF-beta signalling
- pro-peptide (which makes small latent complex/SLC with mature TGF-beta)
- latent TGF-beta binding protein (LTBP) which makes large latent complex with SLC
- fibrillin, collagen, (ECM) important for growth factor activity control
TGF-beta controls
proliferation, differentiation, and other functions in many cell types
TGF-beta two main abilities
- induces cell transformation
- acts as negative autocrine growth factor
Disregulation of TGF beta causes
Marfan syndrome, camurati-engelmann disease and cancer, fibrosis, scleroderma etc
small latent complex (SLC)
TGF beta propeptide bound to TGF beta, and dimerized. Inactive.
Marfan syndrome
- autosomal dominant
- malocclusion, micrognathia, severe periodontal disease, narrow face, tooth crowding
- mutant fibrillin releases TGF-beta (improper activation of growth factor)
Loeys-Dietz syndrome (LDS)
- overlapping symptoms with MFS except:
- low set ears, eyes far apart (hypertelorism)
- bifid uvula, cleft palate - TGF-beta receptors 1 or 2 mutation
Fibrodysplasia ossificans progressiva (FOP)
-BMP receptor (ACVRI/ALK2) mutation
How can mutations in different genes cause the same abnormal phenotypes?
if gene mutations disrupt the same pathways (like in marfan syndrome and LDS), same phenotype could be observed
