Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2(activin receptor-like kinase-2).[5] ACVR1 has been linked to the 2q23-24 region of the genome.[6] This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, a disease characterized by the formation of heterotopic bone throughout the body.[6] It is a bone morphogenetic protein receptor, type 1.
Function[edit]
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors.[7]
Signaling[edit]
ACVR1 transduces signals of BMPs. BMPs bind either ACVR2A/ACVR2B or a BMPR2 and then form a complex with ACVR1. These go on to recruit the R-SMADs SMAD1, SMAD2, SMAD3 or SMAD6.[8]
Clinical significance[edit]
Gain-of-function mutations in the gene ACVR1/ALK2 is responsible for the genetic disease fibrodysplasia ossificans progressiva.[9] The typical FOP patient has the amino acid arginine substituted for the amino acid histidine at position 206 in this protein.[10][11] This causes a change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and thus over-activate the BMP/SMAD pathway.[6]The result of this over-activation is that endothelial cells transform to mesenchymal stem cells and then to bone.[12]Atypical mutations involving other residues work similarly - causing the protein to be stuck in its active conformation despite no BMP being present[13]
Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma(DIPG).[14][15][16]
https://en.wikipedia.org/wiki/ACVR1
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