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This phenomenon is present in the epithelial cells of many organs, and is regulated in part by the Smad signaling pathway. The precise mechanism of control differs slightly between cell types. One mechanism by which Smads facilitate TGF-β induced cytostasis is by downregulating Myc , which is a transcription factor that promotes cell growth.
Type 1 contains a glycine-serine-rich domain to be phosphorylated by type 2 kinase domain, initiating the signaling transduction pathway of the SMAD signaling cascade. [3] The wrist epitope motif on BMP-2 has a high-affinity binding site for BMPR-IA. The knuckle epitope motif on BMP-2 has a low-affinity binding site for BMPR-II. [4]
SARA orients the R-SMAD such that serine residue on its C-terminus faces the catalytic region of the Type I receptor. The Type I receptor phosphorylates the serine residue of the R-SMAD. Phosphorylation induces a conformational change in the MH2 domain of the R-SMAD and its subsequent dissociation from the receptor complex and SARA. [10]
Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. [1] Professor Marshall Urist and Professor Hari Reddi discovered their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body.
BMP4 is also known to activate the ERK, JNK and p38 MAPK signalling pathways whilst have been found to act independently of Smad signaling pathways, are mostly active in conjunction with Smad. [32] The activation of the ERK and JNK pathways acts to phosphorylate Smad and therefore regulate its activation.
TGF-β/SMAD signaling pathway has been shown to have a critical role in the expression of genes controlling differentiation of embryonic stem cells. [15] Some of the developmental genes regulated by this pathway include FGF1, NGF, and WNT11 as well as stem/progenitor cell associated genes CD34 and CXCR4. [16]
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. [ 5 ] [ 6 ] MAD homolog 2 belongs to the SMAD , a family of proteins similar to the gene products of the Drosophila gene ' mothers against decapentaplegic ' (Mad) and the C. elegans gene Sma.
R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-β receptors through their intracellular kinase domain, leading to R-SMAD activation. [1] R-SMADS include SMAD2 and SMAD3 from the TGF-β/Activin/Nodal branch, and SMAD1, SMAD5 and SMAD9 from the BMP/GDP branch of TGF-β signaling. [1]