ALK4

ALK4 (Activin Receptor-Like Kinase 4) or ACVR1B (Activin A Receptor, type 1B), belongs to the protein kinase superfamily, TKL Ser/Thr protein kinase family, and TGFB receptor subfamily. ALK4/ACVR1B acts as a transducer of activin or activin like ligands signals. Activin binds to either ACVR2A or ACVR2B and then forms a complex with ACVR1B. The known type II activin receptors include ActRII and ActRIIB, while the main type I activin receptor in mammalian cells is ALK4 (ActRIB). In the presence of activin, type II and type I receptors form complexes whereby the type II receptors activate ALK4 through phosphorylation. The activated ALK4, in turn, transduces signals downstream by phosphorylation of its effectors, such as Smads, to regulate gene expression and affect cellular phenotype. ALK4/ACVR1B is an important regulator of vertebrate development, with roles in mesoderm induction, primitive streak formation, gastrulation, dorsoanterior patterning, and left-right axis determination.

ALK4 Related Areas

Cancer>>Growth Factor & Receptor>>TGF-beta Superfamily>>Activin/Inhibitin>>ALK4/ACVR1B

Immunology>>Cytokine & Receptor>>TGF-beta Superfamily>>TGF-beta Superfamily Receptors>>ALK4/ACVR1B

ALK4 Related Pathways

• TGF-beta Signaling
• Cytokine Receptor Signaling

ALK4 Alternative Names

ALK-4, ALK4, ACVR1B, ACTRIB, ACVRLK4, SKR2 [Homo sapiens]

ALK-4, Alk4, Acvr1b, ActRIB, ActR-IB, Acvrlk4, SKR2, 6820432J04 [Mus musculus]

Summaries for ALK4

Entrez Gene summary for ALK4:

ACVR1B 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 ALK4 protein is a type I receptor which is essential for signaling. Mutations in ACVR1B gene are associated with pituitary tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

Wikipedia summary for ALK4:

Activin receptor type-1B is a protein that in humans is encoded by the ALK4 gene.

ACVR1B or ALK4 acts as a transducer of activin or activin like ligands (e.g., inhibin) signals. Activin binds to either ACVR2A or ACVR2B and then forms a complex with ALK4. These go on to recruit the R-SMADs SMAD2 or SMAD3.ALK4 also transduces signals of nodal, GDF-1, and Vg1; however, unlike activin, they require other coreceptor molecules such as the protein Cripto.

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 a 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. ALK4 gene encodes activin A type IB receptor, composed of 11 exons. Alternative splicing and alternative polyadenylation result in 3 fully described transcript variants. The mRNA expression of variants 1, 2, and 3 is confirmed, and a potential fourth variant contains an alternative exon 8 and lacks exons 9 through 11, but its mRNA expression has not been confirmed.

Human ALK4 Protein General Information

 

• Protein names: Activin receptor-like kinase 4 ,Short name=ALK4
• Sequence length: 505 AA.
• 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.
• 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.
• 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.
• Cofactor: Magnesium or manganese
• 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.
• Subcellular location: Cell membrane; Single-pass type I membrane protein
• Tissue specificity: Expressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver.
• Involvement in disease: Note=ALK4 is abundantly expressed in systemic sclerosis patient fibroblasts and production of collagen is also induced by activin-A/INHBA. This suggests that the activin/ALK4 signaling mechanism is involved in systemic sclerosis.
• Catalytic activity: ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.
• Enzyme regulation: Activin receptor type-2 (ACVR2A or ACVR2B) activates the type-1 receptor through phosphorylation of its regulatory GS domain.

General information above from UniProt

Function for ALK4 Protein

UniProtKB:

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 ALK4 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 ALK4. 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 ALK4 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. ALK4 also phosphorylates TDP2.

Genatlas:

• ALK4 is the transmembrane receptor involved in protein serine / threonine kinase signaling pathway

Phenotype Information for ALK4

• Gene/Locus: ACVR1B, ACVRLK4, ALK4
• Phenotype: Pancreatic cancer, somatic

Phenotype Information for ALK4 from OMIM (Online Mendelian Inheritance in Man)