Alternative titles; symbols
HGNC Approved Gene Symbol: SMAD1
Cytogenetic location: 4q31.21 Genomic coordinates (GRCh38): 4:145,480,770-145,559,176 (from NCBI)
The SMAD1 gene encodes a protein involved in the downstream signaling pathway of bone morphogenic protein (BMP) subfamily members (e.g., BMP2, 112261) (summary by Han et al., 2013).
Riggins et al. (1996) discussed a family of Mad-related genes in human; see also MADH2 (SMAD2; 601366). Hoodless et al. (1996) cloned the gene encoding a human homolog of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma, which are components of signal transduction pathways. The human gene, symbolized MADR1 by the authors, encodes a 465-amino acid polypeptide that is 76% identical to Drosophila Mad and 42% identical to human DPC4 (600993). Liu et al. (1996) cloned the same human homolog of Sma and Mad and referred to the gene as SMAD1. Both Hoodless et al. (1996) and Liu et al. (1996) showed that the human gene product is phosphorylated and localizes to the nucleus upon activation by bone morphogenic protein (BMP) subfamily members (e.g., BMP2; 112261).
Lechleider et al. (1996) also cloned the human gene, which they symbolized BSP1 for 'TGF-beta (TGFB1; 190180) signaling protein-1,' and demonstrated its role in BMP signal transduction pathways. This gene is also symbolized JV41.
Sapkota et al. (2007) stated that SMAD proteins, including SMAD1, contain 2 conserved functional globular domains (MH1 and MH2) connected by a regulatory linker region. MH1 binds DNA, and MH2 binds membrane receptors for activation, nucleoporins for nuclear translocation, and other SMADs and nuclear factors to form transcriptional complexes. The linker region of SMAD1 contains several sites for phosphorylation by MAP kinases (see ERK2, or MAPK1; 176948) and GSK3-beta (GSK3B; 605004). Downstream of these sites in SMAD1 is a PY motif that binds SMURF ubiquitin ligases (see SMURF1; 605568).
TGFB1 is the prototype of a large family of cytokines that also includes the activins (e.g., 147290), inhibins (e.g., 147380), bone morphogenetic proteins, and mullerian-inhibiting substance (600957). Members of the TGF-beta family exert a wide range of biologic effects on a large variety of cell types; for example, they regulate cell growth, differentiation, matrix production, and apoptosis. Many have important functions during embryonal development in pattern formation and tissue specification; in the adult they are involved in processes such as tissue repair and modulation of the immune system. Heldin et al. (1997) discussed new developments in the understanding of the mechanisms used by members of the TGF-beta family to elicit their effects on target cells. They focused on the pivotal role of SMAD proteins in relaying signals from cell-surface receptors to the nucleus. Pathway-restricted SMADs (e.g., SMAD2 and SMAD3) are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity. They then oligomerize with the common mediator SMAD4 (600993) and translocate to the nucleus where they direct transcription to affect the cell's response to TGF-beta. Inhibitory SMADs had been identified that block the activation of these pathway-restricted SMADs (e.g., SMAD6 and SMAD7).
The cytokines LIF (159540) and BMP2 signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 (102582) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors.
Using human keratinocytes, mouse pluripotent mesenchymal cells, and Xenopus neuroectodermal tissue, Sapkota et al. (2007) showed that FGF (see FGF1; 131220) inhibition of BMP signaling required both phosphorylation of the SMAD1 linker region and SMURF1 function. Binding of SMURF1 to SMAD1 caused SMAD1 polyubiquitination and inhibited SMAD1 binding to the nucleoporin NUP214 (114350). Phosphorylation of serines within the SMAD1 linker region by ERK2 additionally primed the linker region for phosphorylation by the signaling kinase GSK3B, which further facilitated SMAD1 polyubiquitination.
Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta (190180) and BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (see 608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1, SMAD2 (601366), SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; 180630), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not required for this process. Thus, Davis et al. (2008) concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways.
Crystal Structure
Qin et al. (2001) reported the crystal structure of the SMAD1 MH2 domain in a conformation that revealed the structural effects of phosphorylation and a molecular mechanism for activation. Within a trimeric subunit assembly, the SVS sequence docks near 2 putative phosphoserine-binding pockets of the neighboring molecule, in a position ready to interact upon phosphorylation. The MH2 domain undergoes concerted conformational changes upon activation, which signal SMAD1 dissociation from the receptor kinase for subsequent heteromeric assembly with SMAD4. Biochemical and modeling studies revealed unique favorable interactions within the SMAD1/SMAD4 heteromeric interface, providing a structural basis for their association in signaling.
Lechleider et al. (1996) mapped the BSP1 gene to chromosome 4q28 by PCR analysis of somatic cell hybrids and a radiation hybrid panel.
See 601595.0001 for discussion of a possible association between variation in the SMAD1 gene and primary pulmonary hypertension (PPH; see 178600).
Han et al. (2013) found that some mice with conditional knockout of Smad1 in endothelial or smooth muscle cells developed increased pulmonary artery pressure, muscularization of pulmonary arteries, and right ventricular hypertrophy, consistent with pulmonary hypertension. Smad1 deletion in endothelial cells had a greater impact compared to its deletion in smooth muscle cells. Deletion of Bmpr2 (600799) in a murine pulmonary artery endothelial cell line resulted in a decrease in Smad1 phosphorylation by Bmp4 (112262), although phosphorylation by Bmp7 (112267) was unaffected. Bmpr2-deletion was associated with increased TGF-beta-mediated signaling. Overall, the findings indicated that Smad1 is a crucial mediator of Bmpr2 signaling and suggested that an impaired balance between BMP4- and TGF-beta-mediated signaling may account for the pathogenesis of primary pulmonary hypertension.
Using mice with skeletal muscle-specific knockout or knockdown of BMP signaling molecules, Sartori et al. (2013) found that BMP signaling, acting via Smad1, Smad5, and Smad8 (SMAD9; 603295) (Smad1/5/8) and Smad4, regulated muscle mass. Inhibition of BMP signaling caused muscle atrophy, abolished the hypertrophic phenotype of myostatin (MSTN; 601788)-deficient mice, and exacerbated the muscle-wasting effects of denervation and fasting. Bmp14 (GDF5; 601146) was required to prevent excessive muscle loss following denervation. The BMP-Smad1/5/8-Smad4 pathway negatively regulated Fbxo30 (609101), a ubiquitin ligase required for muscle loss. Inhibition of Fbxo30 protected denervated muscle from atrophy and blunted atrophy in Smad4-deficient muscle. Sartori et al. (2013) concluded that BMP signaling is the dominant pathway controlling muscle mass and that the hypertrophic phenotype caused by myostatin inhibition results from unrestrained BMP signaling.
This variant is classified as a variant of unknown significance because its contribution to primary pulmonary hypertension (PPH; see 178600) has not been confirmed.
In a 47-year-old French woman with primary pulmonary hypertension and no family history of the disorder, Nasim et al. (2011) identified a heterozygous c.8T-C transition in exon 1 of the SMAD1 gene, resulting in a val3-to-ala (V3A) substitution at a highly conserved residue upstream of the MH1 domain. SMAD1 was chosen for study because of its role in the BMP signaling pathway (BMPR2 (600799) is mutated in PPH1). The patient's parents were unavailable for study, but the variant was not found in several large control databases or control samples. Overexpression of the mutant protein in a reporter construct generated reduced basal activity and impaired responses to ligand stimulation compared to wildtype. There were no differences in expression of the mutant protein compared to wildtype. Nasim et al. (2011) suggested that the moderate effect of this variant indicates that it may be a susceptibility factor in the development of PPH. The patient died of right heart failure.
Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454: 56-61, 2008. [PubMed: 18548003] [Full Text: https://doi.org/10.1038/nature07086]
Han, C., Hong, K.-H., Kim, Y. H., Kim, M.-J., Song, C., Kim, M. J., Kim, S.-J., Raizada, M. K., Oh, S. P. SMAD1 deficiency in either endothelial or smooth muscle cells can predispose mice to pulmonary hypertension. Hypertension 61: 1044-1052, 2013. [PubMed: 23478097] [Full Text: https://doi.org/10.1161/HYPERTENSIONAHA.111.199158]
Heldin, C.-H., Miyazono, K., ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465-471, 1997. [PubMed: 9393997] [Full Text: https://doi.org/10.1038/37284]
Hoodless, P. A., Haerry, T., Abdollah, S., Stapleton, M., O'Connor, M. B., Attisano, L., Wrana, J. L. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85: 489-500, 1996. [PubMed: 8653785] [Full Text: https://doi.org/10.1016/s0092-8674(00)81250-7]
Lechleider, R. J., de Caestecker, M. P., Dehejia, A., Polymeropoulos, M. H., Roberts, A. B. Serine phosphorylation, chromosomal localization, and transforming growth factor-beta signal transduction by human bsp-1. J. Biol. Chem. 271: 17617-17620, 1996. [PubMed: 8663601] [Full Text: https://doi.org/10.1074/jbc.271.30.17617]
Liu, F., Hata, A., Baker, J. C., Doody, J., Carcamo, J., Harland, R. M., Massague, J. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381: 620-623, 1996. [PubMed: 8637600] [Full Text: https://doi.org/10.1038/381620a0]
Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., Taga, T. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284: 479-482, 1999. [PubMed: 10205054] [Full Text: https://doi.org/10.1126/science.284.5413.479]
Nasim, M. T., Ogo, T., Ahmed, M., Randall, R., Chowdhury, H. M., Snape, K. M., Bradshaw, T. Y., Southgate, L., Lee, G. J., Jackson, I., Lord, G. M., Gibbs, J. S. R., and 10 others. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum. Mutat. 32: 1385-1389, 2011. [PubMed: 21898662] [Full Text: https://doi.org/10.1002/humu.21605]
Qin, B. Y., Chacko, B. M., Lam, S. S., de Caestecker, M. P., Correia, J. J., Lin, K. Structural basis of Smad1 activation by receptor kinase phosphorylation. Molec. Cell 8: 1303-1312, 2001. [PubMed: 11779505] [Full Text: https://doi.org/10.1016/s1097-2765(01)00417-8]
Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. Mad-related genes in the human. Nature Genet. 13: 347-349, 1996. [PubMed: 8673135] [Full Text: https://doi.org/10.1038/ng0796-347]
Sapkota, G., Alarcon, C., Spagnoli, F. M., Brivanlou, A. H., Massague, J. Balancing BMP signaling through integrated inputs into the Smad1 linker. Molec. Cell 25: 441-454, 2007. [PubMed: 17289590] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.006]
Sartori, R., Schirwis, E., Blaauw, B., Bortolanza, S., Zhao, J., Enzo, E., Stantzou, A., Mouisel, E., Toniolo, L., Ferry, A., Stricker, S., Goldberg, A. L., Dupont, S., Piccolo, S., Amthor, H., Sandri, M. BMP signaling controls muscle mass. Nature Genet. 45: 1309-1318, 2013. [PubMed: 24076600] [Full Text: https://doi.org/10.1038/ng.2772]