Alternative titles; symbols
HGNC Approved Gene Symbol: ACVR1B
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:51,951,699-51,997,078 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Pancreatic cancer, somatic | 260350 | 3 |
See ACVRL1 (601284). Human cDNA clones encoding 4 putative transmembrane ser/thr kinases were identified by ten Dijke et al. (1993). Using degenerate DNA primers based on the human activin receptor type II (see 102581) and C. elegans Daf-1 gene products, they PCR-amplified mRNA from human erythroleukemia (HEL) cells, a cell type known to respond both to activin (147290) and TGF-beta (190180). Their partial clone of the ALK4 gene encodes a 383-amino acid polypeptide with a truncated extracellular domain but sequence and structural domain similarities with the other 3 ALK genes they cloned. ALK1, ALK2 (102576), ALK3 (601299), and ALK4 share approximately 40% sequence identity with activin receptors type II and IIB, TGF-beta receptor (see 190181), and Daf-1 in their kinase domains but share 60 to 79% sequence identity among themselves, suggesting to ten Dijke et al. (1993) that the ALK gene products form a subfamily of receptor ser/thr kinases. By Northern analysis, ten Dijke et al. (1993) showed that ALK4 is expressed in many tissues, most strongly in human kidney, pancreas, brain, lung, and liver.
Xu et al. (1994) presented the full amino acid sequence of ACVRLK4 (designated SKR2 by them) and described its genomic organization. They found that different predicted SKR2 gene products are monomers truncated at different kinase subdomains which vary in their kinase activity and potential serine, threonine, and tyrosine phosphorylation sites. The genomic structure and cDNA clones of SKR2 indicated to Xu et al. (1994) that poly(A) addition to alternative exons at each of 3 C-terminal coding exon/intron junctions may be a common feature of both type I and II receptor genes. The researchers suggested that such diversity may add to the heterogeneity of biologic effects from individual ligands in the receptor family.
Xu et al. (1994) determined that the ACVR1B gene contains 11 exons, and they identified alternative exons 8b, 9b, and 10b that are utilized in some ACVR1B splice variants.
Su et al. (2001) determined that the ACVR1B gene comprises 9 exons and spans more than 23 kb.
By Southern blot analysis of DNAs from a somatic cell hybrid mapping panel, Roijer et al. (1998) mapped the ACVR1B gene to chromosome 12. By fluorescence in situ hybridization, they localized the gene to 12q13.
Alexander et al. (1996) reported that several truncated ACVR1B receptor isoforms are exclusively expressed in human pituitary tumors, and that the majority of such tumors did not exhibit activin-induced growth arrest in culture. Zhou et al. (2000) studied the function of these truncated receptor isoforms. Transient expression of these truncated receptors inhibited activin-activated transcription from an activin-responsive reporter construct, 3TPLux. When each of these truncated ACVR1B receptors was stably transfected into K562 cells, activin-induced expression of an endogenous gene, junB (165161), was blocked, indicating that inhibition of gene expression also occurred at the chromosomal level. Furthermore, activin administration failed to cause growth inhibition and an increase of the G1 population in these cells. Coimmunoprecipitation experiments showed that the truncated activin type I receptors formed complexes with type II activin receptors, but were not phosphorylated. Zhou et al. (2000) concluded that the truncated ACVR1B isoforms, predominantly expressed in human pituitary adenomas, function as dominant-negative receptors to interfere with wildtype receptor function and block the antiproliferative effect of activin.
Wang et al. (2008) found that miR24-1 (MIRN24-1; 609705), which was highly expressed in CD34 (142230)-positive human cord blood hematopoietic progenitor cells (HPCs), regulated erythroid differentiation in erythroleukemic K562 cells and HPCs by downregulating the expression of ALK4. miR24-1 decreased ALK4 expression at the mRNA and protein level by binding to at least 1 putative miR24-binding site in the 3-prime untranslated region of ALK4 mRNA, and by reducing ALK4 expression, miR24-1 interfered with activin signaling through SMAD2 (601366) phosphorylation. Stem-loop RT-PCR analysis revealed that expression of mature miR24-1 in HPCs declined 3 days after culturing in differentiation medium, and reduced miR24-1 expression was followed by increased ALK4 expression. Wang et al. (2008) concluded that miR24 inhibits erythroid differentiation and promotes proliferation of HPCs by modulating activin signaling.
DPC4 (600993) is known to mediate signals initiated by beta-transforming growth factor as well as by other TGF-beta superfamily ligands such as activin and bone morphogenic proteins (e.g., 112264). Su et al. (2001) described the gene structure and novel somatic mutations of the activin type IB receptor in pancreatic cancer. This was the first description of ACVR1B as a tumor suppressor gene. They screened for homozygous deletions among 95 pancreatic adenocarcinoma xenografts. They found 1 carrying a homozygous deletion of 657 bp (601300.0002), including the entire exon 8 of ACVR1B. The mutation was somatic and was verified by the study of genomic DNA of normal tissue and primary cancer specimens of the patient. The deletion appeared to be a result of slippage during DNA replication that occurred at a 4-bp repeated sequence. LOH involving the ACVR1B locus was found in 29 of 85 pancreatic cancer xenografts (34%) and in 5 of 11 pancreatic cancer cell lines (45%). A 5-bp deletion (601300.0001) that would cause a frameshift and early termination of protein translation was detected in 1 xenograft. The mutation was somatic and was confirmed in the corresponding primary cancer tissue from the patient.
In a pancreatic cancer (260350) xenograft, Su et al. (2001) found a 5-bp deletion at codon 387 (exon 7) of the ACVR1B gene, causing a frameshift and early termination of protein translation. The mutation was somatic and was confirmed in the corresponding primary cancer tissue from the patient.
In a pancreatic adenocarcinoma (260350) xenograft, Su et al. (2001) found a homozygous deletion of 657 bp, including the entire exon 8 of ACVR1B. The mutation was somatic and was verified by the study of genomic DNA of normal tissue and primary cancer specimens of the patient.
Alexander, J. M., Bikkal, H. A., Zervas, N. T., Laws, E. R., Jr., Klibanski, A. Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas. J. Clin. Endocr. Metab. 81: 783-790, 1996. [PubMed: 8636304] [Full Text: https://doi.org/10.1210/jcem.81.2.8636304]
Roijer, E., Miyazono, K., Astrom, A.-K., Geurts van Kessel, A., ten Dijke, P., Stenman, G. Chromosomal localization of three human genes encoding members of the TGF-beta superfamily of type I serine/threonine kinase receptors. Mammalian Genome 9: 266-268, 1998. [PubMed: 9501322] [Full Text: https://doi.org/10.1007/s003359900745]
Su, G. H., Bansal, R., Murphy, K. M., Montgomery, E., Yeo, C. J., Hruban, R. H., Kern, S. E. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proc. Nat. Acad. Sci. 98: 3254-3257, 2001. [PubMed: 11248065] [Full Text: https://doi.org/10.1073/pnas.051484398]
ten Dijke, P., Ichijo, H., Franzen, P., Schulz, P., Saras, J., Toyoshima, H., Heldin, C.-H., Miyazono, K. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 8: 2879-2887, 1993. [PubMed: 8397373]
Wang, Q., Huang, Z., Xue, H., Jin, C., Ju, X.-L., Han, J.-D. J., Chen, Y.-G. MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 111: 588-595, 2008. [PubMed: 17906079] [Full Text: https://doi.org/10.1182/blood-2007-05-092718]
Xu, J., Matsuzaki, K., McKeehan, K., Wang, F., Kan, M., McKeehan, W. L. Genomic structure and cloned cDNAs predict that four variants in the kinase domain of serine/threonine kinase receptors arise by alternative splicing and poly(A) addition. Proc. Nat. Acad. Sci. 91: 7957-7961, 1994. [PubMed: 8058741] [Full Text: https://doi.org/10.1073/pnas.91.17.7957]
Zhou, Y., Sun, H., Danila, D. C., Johnson, S. R., Sigai, D. P., Zhang, X., Klibanski, A. Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling. Molec. Endocr. 14: 2066-2075, 2000. [PubMed: 11117535] [Full Text: https://doi.org/10.1210/mend.14.12.0570]