UniProt functional annotation for P12643



	UniProt functional annotation for P12643

UniProt code: P12643.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis (PubMed:18436533, PubMed:31019025, PubMed:24362451). Induces cartilage and bone formation (PubMed:3201241). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:15064755, PubMed:17295905, PubMed:18436533). Once all three components are bound together in a complex at the cell surface, BMPR2 phosphorylates and activates BMPR1A (PubMed:7791754). In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes. Can also signal through non-canonical pathways such as ERK/MAP kinase signaling cascade that regulates osteoblast differentiation (PubMed:20851880). Stimulates also the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A-ATF4 pathway by stimulating EIF2A phosphorylation which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation (PubMed:24362451). {ECO:0000269|PubMed:15064755, ECO:0000269|PubMed:17295905, ECO:0000269|PubMed:18436533, ECO:0000269|PubMed:20851880, ECO:0000269|PubMed:24362451, ECO:0000269|PubMed:31019025, ECO:0000269|PubMed:3201241, ECO:0000269|PubMed:7791754}.

Subunit: Homodimer; disulfide-linked (PubMed:10074410). Interacts with SOSTDC1 (PubMed:15020244). Interacts with GREM2, RGMA, RGMB and RGMC. Interacts with ASPN (By similarity). Interacts with MAFP5 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with type I receptor BMPR1A (PubMed:15064755). Interacts with type II receptor BMPR2 (PubMed:7791754). {ECO:0000250|UniProtKB:P21274, ECO:0000269|PubMed:10074410, ECO:0000269|PubMed:15020244, ECO:0000269|PubMed:18339631}.

Subcellular location: Secreted.

Tissue specificity: Particularly abundant in lung, spleen and colon and in low but significant levels in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, prostate, ovary and small intestine.

Disease: Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:19327734, ECO:0000269|PubMed:21357617}. Note=The gene represented in this entry is involved in disease pathogenesis. Duplications of a cis-regulatory element located approximately 110 kb downstream of BMP2 have been found in BDA2 families. They likely cause altered BMP2 expression with pathological consequences. {ECO:0000269|PubMed:19327734, ECO:0000269|PubMed:21357617}.

Disease: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (SSFSC) [MIM:617877]: An autosomal dominant disorder characterized by short stature, facial dysmorphism, skeletal anomalies, and variable cardiac defects. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract. {ECO:0000269|PubMed:29198724}. Note=The disease is caused by variants affecting the gene represented in this entry.

Pharmaceutical: Available under the name Infuse (Medtronic Sofamor Danek). Used for treating open tibial shaft fractures.

Similarity: Belongs to the TGF-beta family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis (PubMed:18436533, PubMed:31019025, PubMed:24362451). Induces cartilage and bone formation (PubMed:3201241). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:15064755, PubMed:17295905, PubMed:18436533). Once all three components are bound together in a complex at the cell surface, BMPR2 phosphorylates and activates BMPR1A (PubMed:7791754). In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes. Can also signal through non-canonical pathways such as ERK/MAP kinase signaling cascade that regulates osteoblast differentiation (PubMed:20851880). Stimulates also the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A-ATF4 pathway by stimulating EIF2A phosphorylation which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation (PubMed:24362451). {ECO:0000269\|PubMed:15064755, ECO:0000269\|PubMed:17295905, ECO:0000269\|PubMed:18436533, ECO:0000269\|PubMed:20851880, ECO:0000269\|PubMed:24362451, ECO:0000269\|PubMed:31019025, ECO:0000269\|PubMed:3201241, ECO:0000269\|PubMed:7791754}.


Subunit:		Homodimer; disulfide-linked (PubMed:10074410). Interacts with SOSTDC1 (PubMed:15020244). Interacts with GREM2, RGMA, RGMB and RGMC. Interacts with ASPN (By similarity). Interacts with MAFP5 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631). Interacts with type I receptor BMPR1A (PubMed:15064755). Interacts with type II receptor BMPR2 (PubMed:7791754). {ECO:0000250\|UniProtKB:P21274, ECO:0000269\|PubMed:10074410, ECO:0000269\|PubMed:15020244, ECO:0000269\|PubMed:18339631}.
Subcellular location:		Secreted.
Tissue specificity:		Particularly abundant in lung, spleen and colon and in low but significant levels in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, prostate, ovary and small intestine.
Disease:		Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269\|PubMed:19327734, ECO:0000269\|PubMed:21357617}. Note=The gene represented in this entry is involved in disease pathogenesis. Duplications of a cis-regulatory element located approximately 110 kb downstream of BMP2 have been found in BDA2 families. They likely cause altered BMP2 expression with pathological consequences. {ECO:0000269\|PubMed:19327734, ECO:0000269\|PubMed:21357617}.
Disease:		Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (SSFSC) [MIM:617877]: An autosomal dominant disorder characterized by short stature, facial dysmorphism, skeletal anomalies, and variable cardiac defects. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract. {ECO:0000269\|PubMed:29198724}. Note=The disease is caused by variants affecting the gene represented in this entry.
Pharmaceutical:		Available under the name Infuse (Medtronic Sofamor Danek). Used for treating open tibial shaft fractures.
Similarity:		Belongs to the TGF-beta family. {ECO:0000305}.