ACVR1 Function in Health and Disease

Abstract

Activin A receptor type I (ACVR1) encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, ACVR1 has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterised by progressive heterotopic ossification. ACVR1 is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, ACVR1 has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG), a malignant childhood brainstem glioma, and its function is being studied in other cancer types. Here, we review ACVR1 receptor function and signalling in physiological and pathological processes and its regulation according to cell type and mutational status. Learning from different functions and alterations linked to ACVR1 is a key step in the development of interdisciplinary research towards the identification of novel treatments for these pathologies.

The context-dependent, combinatorial logic of BMP signaling

“…Therefore, despite extensive molecular characterization, we cannot in general say how specific ligands will function in combinations, why these combinatorial effects vary with context, and what molecular features are necessary to generate the combinatorial and contextual behavior of BMP ligands. Addressing these questions would advance our understanding of the role of BMP signaling components in a variety of skeletal, respiratory, and brain diseases (Salazar, Gamer, and Rosen 2016; Valer et al 2019; Cunha and Pietras 2011) and aid the selection of therapeutic BMPs to selectively induce bone growth in orthopedics and oral surgery (Cicciù et al 2014; Carragee, Hurwitz, and Weiner 2011; Seeherman et al 2019). More generally, it could enable more precise control of cell fate decisions for therapeutic applications and provide insight into the overall logic of cell-cell communication systems.…”

Prognostic Impact of let-7e MicroRNA and Its Target Genes in Localized High-Risk Intestinal GIST: A Spanish Group for Research on Sarcoma (GEIS) Study

“…Overexpression of ACVR1B , a key receptor of bone morphogenetic proteins (BMPs) and an important regulator of the BMP/Wnt signaling pathway and, therefore, for cancer stem cells, was associated with clinically aggressive and poor survival in hepatocellular carcinoma [ 33 ]. The implication of ACVR1B and BMP in cancer has exhibited a dual function according to different cancer cell types or different BMP ligands, promoting or preventing critical cancer hallmarks such as stemness, migration, or proliferation [ 34 ]. Protein expression of Caspase-3, either the cleaved fraction or total protein, was associated with poor prognosis in patients with moderately-differentiated carcinoma of the tongue [ 35 ].…”

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

“…There are also rare, inherited forms of HO, such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH) [ 44 , 45 ]. FOP is autosomal-dominant disorder caused by up to 14 different mutations localised in the type I bone morphogenic protein (BMP) receptor, i.e., activin type 1 receptor (ACVR1; also called activin-like kinase 2, ALK2) gene [ 44 , 46 ]. However, a single mutation, i.e., arginine to histidine at position 206; R206H, is present in the majority of FOP patients [ 44 , 46 ].…”

“…FOP is autosomal-dominant disorder caused by up to 14 different mutations localised in the type I bone morphogenic protein (BMP) receptor, i.e., activin type 1 receptor (ACVR1; also called activin-like kinase 2, ALK2) gene [ 44 , 46 ]. However, a single mutation, i.e., arginine to histidine at position 206; R206H, is present in the majority of FOP patients [ 44 , 46 ]. The ossification of skeletal muscles in FOP occurs mostly in early childhood and is characterized by inflammation-like symptoms and episodical flareups [ 44 ].…”