Bone morphogenetic protein receptors: Structure, function and targeting by selective small molecule kinase inhibitors.
Bone
; 138: 115472, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32522605
ABSTRACT
Bone morphogenetic proteins (BMPs) are secreted cytokines that control the fate and function of many different cell types. They exert their cellular responses via heteromeric complexes of specific BMP type I and type II serine/threonine kinase receptors, e.g. BMPRIA and BMPRII. Three type II and four type I receptors, also termed activin receptor-like kinases (ALKs), have been identified. The constitutively active type II kinase phosphorylates the type I receptor, which upon activation initiates intracellular signaling by phosphorylating SMAD effectors. Auxiliary cell surface receptors without intrinsic enzymatic motifs, such as Endoglin and Repulsive guidance molecules (RGM), can fine-tune signaling by regulating the interaction of the BMP ligands with the BMPRs. The functional annotation of the BMPR encoding genes has helped to understand underlying mechanisms of diseases in which these genes are mutated. Loss of function mutations in BMPRII, Endoglin or RGMc are causally linked to pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia and juvenile hemochromatosis, respectively. In contrast, gain of function mutations in ACVR1, encoding ALK2, are linked to Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Here, we discuss BMPR identification, structure and function in health and disease. Moreover, we highlight the therapeutic promise of small chemical compounds that act as selective BMPR kinase inhibitors to normalize overactive BMPR signaling.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Miositis Osificante
Tipo de estudio:
Guideline
Límite:
Humans
Idioma:
En
Revista:
Bone
Asunto de la revista:
METABOLISMO
/
ORTOPEDIA
Año:
2020
Tipo del documento:
Article