ALK4 (ACTIVIN R1B) Antibody – Mouse Monoclonal

This gene encodes an activin A type IB receptor. 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 and two type II receptors. This protein is a type I receptor which is essential for signaling. Mutations in this gene are associated with pituitary tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

Function: Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2. Ref.2 Ref.9 Ref.10 Ref.13 Ref.16 Ref.19 Ref.20

Catalytic activity: ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.

Cofactor: Magnesium or manganese

By similarity.

Enzyme regulation: Activin receptor type-2 (ACVR2A or ACVR2B) activates the type-1 receptor through phosphorylation of its regulatory GS domain. Ref.11 Ref.14

Subunit structure: Forms an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Interacts with TDP2

By similarity. Interacts with AIP1, FKBP1A, IGSF1, TDGF1, SMAD2, SMAD3 and SMAD7. Ref.2 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.18

Subcellular location: Cell membrane; Single-pass type I membrane protein

By similarity.

Tissue specificity: Expressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver.

Domain: The GS domain is a 30-amino-acid sequence adjacent to the N-terminal boundary of the kinase domain and highly conserved in all other known type-1 receptors but not in type-2 receptors. The GS domain is the site of activation through phosphorylation by the II receptors. Ref.8

Post-translational modification: Autophosphorylated. Phosphorylated by activin receptor type-2 (ACVR2A or ACVR2B) in response to activin-binding at serine and threonine residues in the GS domain. Phosphorylation of ACVR1B by activin receptor type-2 regulates association with SMAD7. Ref.8 Ref.12 Ref.13 Ref.15 Ref.19Ubiquitinated. Level of ubiquitination is regulated by the SMAD7-SMURF1 complex. Ref.18 Ref.21Ubiquitinated.

Involvement in disease: ACVRIB is abundantly expressed in systemic sclerosis patient fibroblasts and production of collagen is also induced by activin-A/INHBA. This suggests that the activin/ACRV1B signaling mechanism is involved in systemic sclerosis.

Sequence similarities: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.Contains 1 GS domain.Contains 1 protein kinase domain.