Affinage

SMAD5

SMAD family member 5 · UniProt Q99717

Length
465 aa
Mass
52.3 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMAD5 is a receptor-regulated SMAD (R-SMAD) that transduces BMP and TGF-β signals from the cell surface to the nucleus, governing a wide range of developmental and homeostatic processes including dorsoventral patterning, hematopoiesis, osteogenesis, angiogenesis, germ cell specification, and iron metabolism. Upon phosphorylation at C-terminal serines by BMP type I receptors (BMPR-IA/IB, ALK3) or ACVR2A, SMAD5 heterodimerizes with SMAD4 and translocates to the nucleus, where its MH1 domain binds both GC-rich sequences and the SMAD-binding element (SBE) via a conserved β-hairpin to activate target genes including Ihh, hepcidin, Eklf, and p21 in cooperation with coactivators such as p300/CBP (PMID:9442019, PMID:26304548, PMID:12857787, PMID:19224984). SMAD5 protein levels are controlled by Smurf1-mediated ubiquitination through a WW2-domain/PPXY-motif interaction and post-transcriptionally by miR-155, whose targeting of SMAD5 in B lymphocytes and DLBCL impairs TGF-β1-induced p21/p15 expression and cell cycle arrest (PMID:12871975, PMID:17676934, PMID:20133617, PMID:24136167). Independent of canonical BMP signaling, cytoplasmic SMAD5 responds to intracellular pH changes via proton dissociation from MH1 domain residues, physically interacts with hexokinase 1, and accelerates glycolysis, revealing a non-transcriptional metabolic function (PMID:28675158).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Establishing SMAD5 as a BMP pathway effector: it was unknown which intracellular mediators transduced BMP signals; overexpression and dominant-negative truncation experiments showed SMAD5 acts downstream of BMPR-IB to switch C2C12 cells from myogenic to osteoblastic differentiation, and SMAD5 requires SMAD4 as a co-factor in Xenopus dorsoventral patterning.

    Evidence Dominant-negative SMAD5 truncations in C2C12 cells; epistasis with dominant-negative SMAD4 in Xenopus embryos

    PMID:9133445 PMID:9299554

    Open questions at the time
    • Direct receptor–SMAD5 interaction not yet biochemically demonstrated
    • DNA-binding properties of SMAD5 unknown
  2. 1998 High

    Defining the activation mechanism: BMP-2 and OP-1/BMP-7 were shown to induce serine phosphorylation of SMAD5 through direct physical association with BMPR-IA/IB, and phosphorylated SMAD5 forms a complex with SMAD4 that translocates to the nucleus; a C-terminal serine-to-alanine mutant acts as a dominant negative.

    Evidence Co-immunoprecipitation with BMP receptors, phosphorylation assays, dominant-negative mutagenesis in C2C12 and ROB-C26 cells

    PMID:9442019 PMID:9766532

    Open questions at the time
    • Structural basis of DNA recognition unresolved
    • Identity of direct transcriptional targets unknown
  3. 1999 High

    Genetic validation of SMAD5 essentiality in vivo: Smad5 knockout mice die at E9.5–E11.5 with angiogenesis defects and mesenchymal apoptosis, and the zebrafish somitabun mutation mapped to SMAD5's L3 loop acts as an antimorph, confirming SMAD5 is indispensable for BMP-mediated dorsoventral patterning and vascular development.

    Evidence Homologous recombination knockout in mouse; genetic mapping and double-mutant analysis in zebrafish

    PMID:10079220 PMID:10079226 PMID:10207140

    Open questions at the time
    • Tissue-specific requirements of SMAD5 not yet dissected
    • Functional redundancy with SMAD1/SMAD8 not quantified
  4. 2000 High

    Expanding developmental roles: Smad5 mutant mice showed left-right patterning defects with bilateral nodal/lefty-2 and absent lefty-1 expression, and a truncated splice isoform SMAD5β lacking the MH2 domain was identified in CD34+ stem cells, raising the possibility of isoform-specific regulation.

    Evidence Whole-mount in situ hybridization in Smad5 KO embryos; RT-PCR and yeast two-hybrid characterization of SMAD5β

    PMID:10677256 PMID:10845932

    Open questions at the time
    • SMAD5β functional significance not established by loss-of-function
    • Mechanism of left-right signaling through SMAD5 not resolved
  5. 2001 High

    SMAD5 was placed in primordial germ cell specification and its DNA-binding specificity was defined: Smad5 KO embryos lack PGCs similarly to Bmp4/Bmp8b mutants; SELEX revealed the MH1 domain binds both the SBE (GTCTAGAC) and GC-rich motifs, distinguishing it from SMAD1/SMAD8.

    Evidence Oct4 in situ in Smad5 KO embryos; SELEX with GST-SMAD5 MH1 fusion

    PMID:11404080 PMID:11527422

    Open questions at the time
    • No crystal structure to explain dual DNA-binding specificity
    • Chromatin context of SMAD5 binding unexplored
  6. 2002 High

    SMAD5 was established as a key regulator of hematopoiesis: it mediates BMP4-induced erythroid differentiation of CD34+ cells, and Smad5-null embryonic progenitors show enhanced proliferation with decreased TGF-β1 sensitivity and altered GATA-2/AML1 expression, defining SMAD5 as a negative regulator of multipotential progenitor expansion.

    Evidence Antisense knockdown in CD34+ cells; Smad5 KO ES cell embryoid body differentiation with colony assays

    PMID:12064918 PMID:12393578

    Open questions at the time
    • Direct transcriptional targets in hematopoietic progenitors not identified by ChIP
    • SMAD5 IRES translational regulation not linked to hematopoietic function
  7. 2003 High

    Protein turnover mechanism resolved: Smurf1 was identified as the E3 ubiquitin ligase that selectively targets SMAD5 (not SMAD2/3/7) for proteasomal degradation, shifting the myogenic-osteogenic cell fate balance; SMAD5 restoration rescues BMP-mediated osteoblast conversion.

    Evidence Smurf1 overexpression and siRNA knockdown with SMAD5 rescue in C2C12 cells

    PMID:12871975

    Open questions at the time
    • Specific ubiquitination sites on SMAD5 not mapped
    • Structural basis of Smurf1–SMAD5 selectivity unknown
  8. 2004 High

    SMAD5 was linked to stress erythropoiesis and shown to have non-redundant functions: the flexed-tail mouse maps to Smad5 and fails to mount a stress erythropoietic response; SMAD5 (not SMAD1) is specifically phosphorylated by BMP2 in cerebellar granule neurone precursors; and compound Smad1+/−;Smad5+/− heterozygotes demonstrate cooperativity.

    Evidence Genetic mapping of flexed-tail to Smad5; in vivo phosphorylation in cerebellar neurons; compound heterozygote analysis in mouse

    PMID:15197161 PMID:15591122 PMID:16765933

    Open questions at the time
    • Molecular basis for SMAD5 vs. SMAD1 selectivity at the receptor level unclear
    • Stress erythroid progenitor-specific targets of SMAD5 unidentified
  9. 2007 High

    Structural determinants of SMAD5 degradation and non-redundant hematopoietic functions clarified: the Smurf1 WW2 domain binds the PPXY motif in the SMAD5 linker for ubiquitination; in zebrafish, SMAD5 is uniquely required for primitive erythropoiesis (SMAD1 for macrophages), and cross-rescue experiments prove inherently distinct activities.

    Evidence In vitro ubiquitination assay with WW2 deletion mutants; morpholino knockdown with reciprocal rescue in zebrafish

    PMID:17676934 PMID:17761518

    Open questions at the time
    • In vivo ubiquitination dynamics of SMAD5 not characterized
    • Transcriptional targets unique to SMAD5 vs. SMAD1 in hematopoiesis not comprehensively defined
  10. 2010 High

    Post-transcriptional regulation by miR-155 identified: miR-155 directly targets SMAD5 3′UTR, making DLBCL cells resistant to TGF-β1 and BMP growth inhibition by suppressing p21 induction and cell cycle arrest, revealing a non-canonical TGF-β1–SMAD5 signaling module in B lymphocytes.

    Evidence Genome-wide miRNA screen, luciferase 3′UTR reporter, RNAi phenocopy in DLBCL cells and in vivo

    PMID:20133617

    Open questions at the time
    • Mechanism by which TGF-β1 activates SMAD5 (non-canonical route) not fully elucidated
    • Other miRNAs targeting SMAD5 in hematopoiesis not systematically cataloged
  11. 2012 High

    A novel antagonistic mechanism between BMP and Nodal signaling was uncovered: BMP4 induces formation of an unusual SMAD2/SMAD5 heteromeric complex that interferes with the Nodal–SMAD2/4–Foxh1 autoregulatory loop; loss of SMAD5 leads to ectopic primitive streak formation due to unrestrained Nodal signaling.

    Evidence Co-immunoprecipitation of SMAD2/SMAD5 complex after BMP4 stimulation; Smad5 KO mouse phenotypic analysis

    PMID:22912414

    Open questions at the time
    • Stoichiometry and DNA-binding behavior of SMAD2/SMAD5 complex not resolved
    • Whether this mechanism operates in adult tissues unknown
  12. 2015 High

    Structural basis of dual DNA recognition resolved: X-ray crystallography of the SMAD5 MH1 domain in complex with GC-rich and SBE DNA revealed that the same β-hairpin contacts both sequences through distinct interaction modes, with DNA spacer length affecting MH1 assembly on composite elements.

    Evidence X-ray crystal structures of SMAD5 MH1–DNA complexes

    PMID:26304548

    Open questions at the time
    • Full-length SMAD5 structure not available
    • How chromatin context modulates MH1 binding preferences in vivo unresolved
  13. 2017 High

    A BMP-independent metabolic function was discovered: intracellular pH changes cause proton dissociation from MH1 domain residues, driving SMAD5 from nucleus to cytoplasm where it physically interacts with hexokinase 1 and accelerates glycolysis; SMAD5 ablation causes chronic bioenergetic dysregulation rescued only by cytoplasmic SMAD5.

    Evidence Live-cell imaging under pH-altering conditions, SMAD5 KO with cytoplasm-restricted rescue, hexokinase 1 Co-IP, glycolysis assay

    PMID:28675158

    Open questions at the time
    • Structural details of SMAD5–hexokinase 1 interface unknown
    • Physiological contexts where pH-dependent SMAD5 shuttling is rate-limiting for glycolysis not defined
    • Whether other R-SMADs share this metabolic function untested
  14. 2019 High

    Tissue-specific roles in iron homeostasis and endometrial biology defined: hepatocyte SMAD1/5 are required for hepcidin production and iron regulation, with triple Smad1/5/8 KO causing severe iron overload; endometrial SMAD1/5 deletion via ACVR2A causes gland hyperplasia and infertility.

    Evidence Hepatocyte- and endometrium-specific conditional knockouts with molecular and functional readouts

    PMID:31127639 PMID:34099644

    Open questions at the time
    • Direct SMAD5 chromatin occupancy at the hepcidin promoter not shown by ChIP
    • Relative individual contributions of SMAD1 vs. SMAD5 in endometrium not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the full-length structure of SMAD5 and how its linker region integrates phosphorylation, ubiquitination, and protein–protein interaction signals; the genome-wide direct transcriptional targets of SMAD5 versus SMAD1 that explain their non-redundant functions; and the physiological significance of the pH-dependent cytoplasmic SMAD5–hexokinase 1 metabolic axis in organismal energy homeostasis.
  • No full-length SMAD5 structure
  • Genome-wide ChIP-seq comparing SMAD5 vs. SMAD1 occupancy not reported
  • In vivo relevance of SMAD5–hexokinase 1 interaction to whole-body metabolism untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2
Partners
BMPR1ABMPR1BCOPS5HK1SMAD1SMAD2SMAD4SMURF1
Complex memberships
SMAD2–SMAD5 heteromeric complexSMAD5–SMAD4 heteromeric complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 BMP-2 causes serine phosphorylation of SMAD5 via direct physical association with BMP type Ia or Ib receptors; following phosphorylation, SMAD5 binds to SMAD4 (DPC4) and the complex translocates to the nucleus. Point mutation G419S in SMAD5 or C-terminal deletion of SMAD4 blocks osteoblastic differentiation of C2C12 cells. Co-immunoprecipitation, serine phosphorylation assay, dominant-negative mutagenesis, alkaline phosphatase activity assay, osteocalcin production assay in C2C12 cells The Journal of biological chemistry High 9442019
1997 SMAD5 (and SMAD1) act downstream of BMP-2 receptor signaling to inhibit myogenic differentiation and induce osteoblast differentiation in C2C12 myoblasts; C-terminal-truncated SMAD1 and SMAD5 block BMP signals from constitutively active BMPR-IB, restoring myogenin promoter activity. Transient transfection of wild-type and C-terminal truncated SMAD constructs, alkaline phosphatase activity assay, myogenin-CAT reporter assay in C2C12 cells Biochemical and biophysical research communications High 9299554
1997 SMAD5 misexpression in Xenopus embryos causes ventralization and induces ventral mesoderm and epidermis; these activities require SMAD4 (DPC4) activity, placing SMAD5 downstream of BMP4 signaling and requiring SMAD4 as co-factor. mRNA microinjection in Xenopus embryos, dominant-negative SMAD4 co-injection, animal cap assays Developmental biology High 9133445
1998 SMAD5 mediates osteogenic protein-1 (OP-1/BMP-7) signaling: SMAD5 stably interacts with kinase-deficient BMPR-IB after it is phosphorylated by BMPR-II; OP-1 stimulates SMAD5 phosphorylation in ROB-C26 osteoprogenitor cells; a SMAD5-2SA dominant-negative mutant (C-terminal serine-to-alanine) blocks OP-1 responses. Co-immunoprecipitation with kinase-deficient receptor, phosphorylation assay, dominant-negative SMAD5-2SA transfection, transcriptional reporter assay Journal of cellular physiology High 9766532
1999 In zebrafish, the somitabun (sbn) mutation is a single amino acid change in the L3 loop of SMAD5 that transforms it into an antimorphic version inhibiting wild-type SMAD5 and related SMADs; double mutant analyses show SMAD5 acts downstream of BMP2b signaling to mediate BMP2b autoregulation during dorsoventral patterning. Genetic mapping, dominant negative characterization, double-mutant analysis, RNA injection rescue experiments in zebrafish Development (Cambridge, England) High 10207140
1999 SMAD5 knockout mice die between E9.5-E11.5 with defects in angiogenesis; mutant embryos have enlarged blood vessels surrounded by decreased numbers of vascular smooth muscle cells, massive mesenchymal apoptosis, and inability to direct angiogenesis in vitro, indicating SMAD5 regulates endothelium-mesenchyme interactions. Homologous recombination knockout, histology, in vitro angiogenesis assay, embryo morphology analysis Development (Cambridge, England) High 10079220 10079226
1998 SMAD5 mediates the inhibitory effects of TGF-β on human hematopoietic progenitor cell proliferation; antisense oligonucleotides to SMAD5 reverse TGF-β1 and TGF-β2-mediated inhibition of myeloid, erythroid, megakaryocyte and multilineage colony formation from CD34+ cells. Antisense oligonucleotide knockdown, hematopoietic colony formation assay in CD34+ human bone marrow cells Blood Medium 9490674
2000 SMAD5 is required for left-right axis determination in mice; Smad5 mutant embryos exhibit defects in heart looping and embryonic turning, with lefty-1 expression absent and nodal, lefty-2, and Pitx2 expressed bilaterally, placing SMAD5 upstream of lefty-1, nodal, and lefty-2 in the L-R patterning cascade. Smad5 knockout mouse analysis, whole-mount in situ hybridization for lefty-1, lefty-2, nodal, Pitx2 Developmental biology High 10677256
2001 SMAD5 is required for primordial germ cell (PGC) development; Smad5 mutant mice show greatly reduced or absent PGCs (similar to Bmp4 or Bmp8b mutants), and some mutants have ectopic PGC-like cells in the amnion, placing SMAD5 downstream of BMP4/BMP8b in PGC specification. Oct4 whole-mount in situ hybridization, alkaline phosphatase staining in Smad5 knockout embryos Mechanisms of development High 11404080
2001 The MH1 domain of SMAD5 binds a consensus sequence GTCTAGAC (Smad-binding element, SBE) and also TGTGC; SMAD5 uniquely has DNA-binding properties similar to SMAD3 (binding the SBE) unlike the closely related SMAD1 and SMAD8, identified by SELEX with GST-SMAD5 N-terminal fusion protein. SELEX (systematic evolution of ligands by exponential enrichment) with GST-Smad5 MH1 fusion protein, mutational analysis of SBE binding Biochemical and biophysical research communications Medium 11527422
2002 SMAD5 is required for BMP4-induced erythroid differentiation of human CD34+ hematopoietic progenitors; BMP4 activates SMAD5 phosphorylation, nuclear translocation, and specific transcription responses; antisense SMAD5 knockdown blocks BMP4-induced erythroid (but not granulocyte-macrophage) differentiation. Antisense oligonucleotide knockdown, Western blot for SMAD5 phosphorylation and nuclear translocation, colony formation assay, glycophorin-A+ cell quantification Blood cells, molecules & diseases Medium 12064918
2002 Loss of Smad5 leads to enhanced proliferation of high-proliferative potential colony-forming cells (HPP-CFCs) during embryonic hematopoiesis with gene-dosage effect; Smad5-/- HPP-CFCs show decreased sensitivity to TGF-β1 inhibition and altered expression of GATA-2 and AML1, defining SMAD5 as a negative regulator of embryonic multipotential hematopoietic progenitors. Smad5 knockout ES cell differentiation, embryoid body colony assays, TGF-β1 inhibition assay, RT-PCR for transcription factor expression Blood High 12393578
2003 Smurf1, an E3 ubiquitin ligase, specifically targets SMAD5 for degradation; elevated Smurf1 markedly reduces endogenous SMAD5 protein but not SMAD2, SMAD3, or SMAD7; this selective degradation promotes myogenic differentiation and blocks BMP-induced osteogenic conversion; restoring SMAD5 from an exogenous source rescues BMP-mediated osteoblast conversion. Smurf1 overexpression, siRNA knockdown of endogenous Smurf1, rescue experiment with exogenous SMAD5, Western blot quantification of endogenous SMADs in C2C12 cells The Journal of biological chemistry High 12871975
2003 BMP4 produced by Sertoli cells signals through ALK3 receptor and SMAD5 in spermatogonia; BMP4 stimulation of spermatogonia induces SMAD4/5 nuclear translocation and formation of a DNA-binding complex with p300/CBP transcriptional coactivator; BMP4 induces both mitogenic and differentiative (Kit expression) effects in undifferentiated spermatogonia. Immunofluorescence for nuclear translocation, co-immunoprecipitation with p300/CBP, [3H]thymidine incorporation, Kit expression analysis in cultured spermatogonia Journal of cell science Medium 12857787
2004 BMP4/SMAD5 (Madh5)-dependent signaling, regulated by hypoxia, initiates the differentiation and expansion of stress erythroid progenitors in the spleen during acute anemia; flexed-tail (f) mutant mice have a mutation in Madh5 (Smad5) and cannot rapidly respond to acute erythropoietic stress. Genetic mapping of the flexed-tail mutation to Smad5, mouse phenotypic analysis of stress erythropoiesis, hypoxia regulation studies Blood High 15591122
2004 BMP2 specifically phosphorylates SMAD5 (not SMAD1) in cerebellar granule neurone precursors; overexpression of SMAD5 alone is sufficient to induce granule cell differentiation even in the presence of Shh; this places SMAD5 as the mediator of BMP2 antagonism of Shh-induced proliferation. In vivo phosphorylation analysis, immunohistochemistry, SMAD5 overexpression in primary cerebellar cultures, Shh proliferation assay Development (Cambridge, England) High 15197161
2004 SMAD1 and SMAD5 together govern BMP target gene expression in early mammalian embryo; Smad1+/-:Smad5+/- double heterozygotes die by E10.5 with defects in allantois morphogenesis, cardiac looping and PGC specification, demonstrating cooperative function of SMAD1 and SMAD5. Genetic compound heterozygosity analysis, embryo phenotyping, whole-mount analysis of BMP targets Developmental biology High 16765933
2004 Smurf1 overexpression specifically reduces SMAD1 and SMAD5 protein levels (but not SMAD8) via ubiquitin-mediated degradation in embryonic lung epithelium; this inhibits BMP4-stimulated branching morphogenesis that can be rescued by SMAD1 co-expression. Adenoviral overexpression of Smurf1 in lung explants, Western blot for SMAD1/5/8 protein levels, BMP4 rescue experiment, lung branching morphology quantification American journal of physiology. Lung cellular and molecular physiology Medium 14711801
2007 Smurf1 WW2 domain interacts with the PPXY motif in the linker region of SMAD5; deletion of the WW2 domain abolishes Smurf1 binding to SMAD5 and its ubiquitination activity on SMAD1 in vitro, demonstrating that PPXY-WW domain interaction is required for Smurf1-mediated ubiquitination of SMAD5. Purified recombinant protein binding assay, WW2 domain deletion mutant analysis, in vitro ubiquitination assay, molecular docking Journal of biomolecular structure & dynamics Medium 17676934
2007 SMAD5 (not SMAD1) is required for primitive erythropoiesis in zebrafish embryos, while SMAD1 is required for macrophage production; both are required for definitive hematopoietic progenitor generation; SMAD5 cannot rescue SMAD1 loss-of-function, demonstrating inherently distinct activities; SMAD5 uniquely regulates the BMP signaling pathway itself. Morpholino knockdown in zebrafish, hematopoietic cell quantification, rescue experiments with SMAD1 vs SMAD5 mRNA, microarray gene expression analysis Blood High 17761518
2007 Deletion of SMAD5 in cardiomyocytes (via Sm22-Cre) leads to decreased cardiac contractility with larger left ventricle internal diameters and decreased fractional shortening at 9 months, demonstrating SMAD5 is required for cardiac homeostasis; deletion restricted to endothelial or smooth muscle cells does not affect vasculature. Cre-loxP tissue-specific knockout, echocardiographic analysis, treadmill performance, isolated cardiomyocyte fractional shortening measurement The American journal of pathology High 17456754
2008 Gata2 and Smad5 cooperate to induce Eklf expression in hematopoietic progenitors prior to erythroid commitment; after erythroid commitment, Gata1 takes over Eklf regulation; established by in vivo ChIP binding studies and loss-of-function in embryoid bodies. Transgenic reporter assays, phylogenetic footprinting, in vivo chromatin immunoprecipitation (ChIP), loss-of-function in embryoid bodies Development (Cambridge, England) Medium 18448565
2008 BMP4/Smad5-dependent stress erythropoiesis pathway drives expansion of a specific population of stress erythroid progenitors in fetal liver; defects in BMP4/Smad5 signaling preferentially affect stress erythroid progenitors causing fetal anemia. flexed-tail (Smad5 mutant) mice analysis, characterization of two erythroid progenitor populations in fetal liver, BMP4 signaling analysis Developmental biology Medium 18374325
2009 BMP canonical Smad signaling through SMAD1 and SMAD5 (but not SMAD8) is required for endochondral bone formation; combined cartilage-specific Smad1/5 knockout causes severe chondrodysplasia; Ihh is a direct transcriptional target of BMP/SMAD1/5 pathway in chondrocytes. Cartilage-specific conditional knockout (Cre-loxP), skeletal analysis, gene expression studies, pathway cross-talk analysis Development (Cambridge, England) High 19224984
2010 miR-155 directly targets SMAD5, rendering DLBCL cells resistant to TGF-β1 and BMP growth-inhibitory effects; a noncanonical signaling module linking TGF-β1 to SMAD5 is active in DLBCL; miR-155-mediated SMAD5 suppression impairs p21 induction and cell cycle arrest. Genome-wide microRNA target screen, luciferase reporter assay, RNAi-based SMAD5 knockdown in vitro and in vivo, p21 and cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 20133617
2011 KSHV-encoded miR-K12-11 directly targets SMAD5, downregulating TGF-β signaling and facilitating cell proliferation upon TGF-β treatment; this was confirmed in de novo KSHV infection and latently infected cells; restoration of SMAD5 sensitized BC3 cells to TGF-β cytostatic effects. miR-K12-11 ectopic expression, luciferase 3'UTR reporter assay, miRNA sponge inhibitor, de novo infection system, TGF-β growth assay Journal of virology Medium 22013049
2012 BMP/SMAD5 signaling antagonizes Nodal signaling by interfering with the Nodal-SMAD2/4-Foxh1 autoregulatory pathway through formation of an unusual BMP4-induced SMAD complex containing both SMAD2 and SMAD5; loss of SMAD5 causes ectopic primitive streak formation in the amnion due to aberrant Nodal activity. Smad5 knockout mouse analysis, cell culture BMP4 stimulation, co-immunoprecipitation to detect SMAD2/SMAD5 complex, quantitative gene expression analysis Development (Cambridge, England) High 22912414
2013 miR-155 targeting of SMAD5 blunts TGF-β1-induced transcription of p15 and p21, sustaining RB phosphorylation and inactivity; SMAD5 levels are elevated in miR-155 KO B lymphocytes which show heightened TGF-β1 sensitivity with suppression of RB phosphorylation and G0/G1 arrest. miR-155 KO mouse, DLBCL cell lines with ectopic miR-155, genetic knockdown of SMAD5/p15/p21, RB phosphorylation assay, pRB-E2F1 complex analysis, cell cycle analysis Blood High 24136167
2013 c-Abl tyrosine kinase associates with BMP receptor IA and regulates phosphorylation of SMAD5 in response to BMP-2; inhibition of c-Abl suppresses BMP receptor-specific SMAD-dependent transcription of CSF-1, osterix, and BMP-2 in osteoblast differentiation. Co-immunoprecipitation of c-Abl with BMPR-IA, dominant-negative c-Abl mutant, c-Abl null calvarial osteoblasts, pharmacological inhibitor (imatinib), transcriptional reporter assays The Journal of biological chemistry Medium 23821550
2014 In zebrafish, SMAD1 and SMAD9 act redundantly downstream of SMAD5 to mediate ventral specification; smad1 and smad9 are direct transcriptional targets of SMAD5; dorsalization caused by smad5 knockdown can be fully rescued by smad1 or smad9 overexpression, but dorsalization from smad1/smad9 double knockdown cannot be rescued by smad5. Morpholino knockdown (single and double), mRNA rescue injections, epistasis analysis, transcription factor binding studies in zebrafish The Journal of biological chemistry High 24488494
2015 Crystal structure of SMAD5 MH1 domain in complex with GC-rich DNA sequence and SBE reveals that the same β-hairpin contacts both DNA sequences with different interaction modes; Conserved β-hairpin residues make base-specific contacts with minimal GC-rich site 5'-GGC-3'; MH1 domain binds each site with modular binding modes, and DNA spacer length affects MH1 assembly. X-ray crystallography of SMAD5 MH1 domain complexed with GC-rich DNA and SBE DNA Nucleic acids research High 26304548
2017 SMAD5 responds to intracellular pH (pHi) changes independent of BMP signaling: increased pHi (cold, basic, hypertonic conditions) causes dissociation of protons from charged amino acid clusters in the MH1 domain, prompting SMAD5 relocation from nucleus to cytoplasm; decreased pHi blocks nuclear export causing nuclear accumulation. Cytoplasmic SMAD5 physically interacts with hexokinase 1 and accelerates glycolysis; SMAD5 ablation causes chronic bioenergetic dysregulation that is rescued only by cytoplasmic SMAD5. Live-cell imaging of SMAD5 localization under pH-altering conditions, SMAD5 KO cells, rescue with cytoplasm-restricted SMAD5, hexokinase 1 Co-IP, glycolysis assay Cell research High 28675158
2019 Hepatocyte SMAD1/5 are major regulators of hepcidin production in response to iron; EGF fails to suppress hepcidin in Smad1/5 knockout hepatocytes; SMAD1/5/8 are required for hepcidin regulation by testosterone but not by inflammation; triple Smad1/5/8 knockout causes more severe iron overload than Smad1/5 double knockout, establishing redundant roles. Hepatocyte-specific conditional KO (Alb-Cre), iron loading measurements, hepcidin expression assays, EGF and LPS stimulation of isolated hepatocytes Hepatology (Baltimore, Md.) High 31127639
2021 BMP signaling occurs via a conserved ACVR2A-SMAD1/5 axis in the endometrium; SMAD1/5 conditional deletion causes cystic endometrial glands, hyperproliferative epithelium, impaired apicobasal transformation, and infertility; ACVR2A (not ACVR2B) is the upstream receptor mediating this pathway. Conditional KO with PR-Cre (single and double SMAD1/5, ACVR2A, ACVR2B), endometrial histology, implantation analysis Nature communications High 34099644
2006 Jun activation domain-binding protein 1 (Jab1) is a novel SMAD5 interactor in chondrocytes; Jab1 was identified by yeast two-hybrid from human articular cartilage cDNA library, confirmed by co-immunoprecipitation; Jab1 overexpression attenuates BMP-dependent transcriptional responses, acting as an inhibitor of BMP signaling. Yeast two-hybrid screen, co-immunoprecipitation, BMP-dependent transcriptional reporter assay Arthritis and rheumatism Medium 17133595
2010 SMAD5 transcriptionally regulates Akt2 expression in L6 myotubes; SMAD5 knockdown decreases Akt2 expression and serine phosphorylation, impairs insulin-induced glucose uptake, and increases Ship2 expression; SMAD5 binds to the Akt2 gene promoter (demonstrated by ChIP); SMAD5 (not SMAD1/8) is downregulated by dexamethasone both in vivo and in vitro. siRNA knockdown, chromatin immunoprecipitation (ChIP) of Smad5 at Akt2 gene, glucose uptake assay, Western blot for Akt2 and phospho-Akt2, in vivo dexamethasone treatment Molecular and cellular endocrinology Medium 20079400
2011 Loss of SMAD5 in intestinal epithelium (Smad5-ΔIEC mice) leads to hypermigration, displacement of E-cadherin from the apical junctional complex to cytoplasm, deregulation of claudin-1/2, and increased susceptibility to DSS-induced colitis with impaired wound healing, demonstrating SMAD5 maintains apical junctional complex integrity. Intestine-specific conditional KO, immunofluorescence, Western blot for claudin-1/2 and E-cadherin localization, DSS colitis model, wound healing assay American journal of physiology. Gastrointestinal and liver physiology High 21212325
2019 lncRNA TUG1 directly binds to the 50-90 aa region of SMAD5 protein and blocks nuclear translocation of phosphorylated SMAD5 after irradiation, suppressing osteogenic signaling; established by RIP assay and SMAD5 deletion mapping. RNA immunoprecipitation (RIP) assay, SMAD5 deletion series to map TUG1 binding site, immunofluorescence of p-SMAD5 nuclear translocation, Western blot Theranostics Medium 31149038
2002 The 5'UTR of SMAD5 mRNA contains an internal ribosome entry site (IRES) located within 100 nt of the 3' end; Smad5 IRES is 4-8-fold more active than poliovirus IRES in C2C12 cells but less active in 293T cells, demonstrating cell-type specific IRES activity requiring a nuclear event for efficient translation initiation. Dicistronic reporter constructs, in vitro transcription and transfection, comparison of DNA versus in vitro transcript IRES activity in C2C12 and 293T cells Nucleic acids research Medium 12087169
2000 A novel SMAD5 splice isoform, SMAD5β, encodes a 351 aa protein with a truncated MH2 domain and unique 18 aa C-terminal tail; SMAD5β lacks physical interactions with SMAD5 or SMAD4 (yeast two-hybrid); higher SMAD5β levels in CD34+ hematopoietic stem cells than in differentiated leukocytes, suggesting a role in protecting stem cells from BMP-induced differentiation. RT-PCR identification of novel splice form, yeast two-hybrid interaction assay, comparative expression in CD34+ vs. peripheral blood cells Blood Medium 10845932

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development (Cambridge, England) 346 10079226
1999 Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development (Cambridge, England) 313 10079220
2009 BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development (Cambridge, England) 297 19224984
1998 Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. The Journal of biological chemistry 260 9442019
2007 Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice. Molecular and cellular biology 179 17967875
1997 Smad1 and smad5 act downstream of intracellular signalings of BMP-2 that inhibits myogenic differentiation and induces osteoblast differentiation in C2C12 myoblasts. Biochemical and biophysical research communications 179 9299554
2010 Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proceedings of the National Academy of Sciences of the United States of America 175 20133617
1999 The smad5 mutation somitabun blocks Bmp2b signaling during early dorsoventral patterning of the zebrafish embryo. Development (Cambridge, England) 169 10207140
2003 Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation. Journal of cell science 167 12857787
2004 BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 166 15591122
2001 Smad5 is required for mouse primordial germ cell development. Mechanisms of development 155 11404080
1997 Smad5 induces ventral fates in Xenopus embryo. Developmental biology 143 9133445
2006 Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo. Developmental biology 130 16765933
2019 Lnc SMAD5-AS1 as ceRNA inhibit proliferation of diffuse large B cell lymphoma via Wnt/β-catenin pathway by sponging miR-135b-5p to elevate expression of APC. Cell death & disease 124 30874550
2004 Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development (Cambridge, England) 123 15197161
2000 Smad5 is essential for left-right asymmetry in mice. Developmental biology 113 10677256
2002 Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interactions with Smad1 and Smad5. Bone 108 12151083
2015 miR-23a and miR-27a promote human granulosa cell apoptosis by targeting SMAD5. Biology of reproduction 106 26400397
2020 Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. Journal of nanobiotechnology 103 32178675
2017 MicroRNA-21 regulates Osteogenic Differentiation of Periodontal Ligament Stem Cells by targeting Smad5. Scientific reports 83 29192241
2011 Kaposi's sarcoma-associated herpesvirus-encoded microRNA miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5. Journal of virology 80 22013049
2004 Spatio-temporal activation of Smad1 and Smad5 in vivo: monitoring transcriptional activity of Smad proteins. Journal of cell science 76 15331632
1998 The Smad5 gene is involved in the intracellular signaling pathways that mediate the inhibitory effects of transforming growth factor-beta on human hematopoiesis. Blood 75 9490674
1998 Intracellular signaling of osteogenic protein-1 through Smad5 activation. Journal of cellular physiology 72 9766532
2003 Smurf1 facilitates myogenic differentiation and antagonizes the bone morphogenetic protein-2-induced osteoblast conversion by targeting Smad5 for degradation. The Journal of biological chemistry 71 12871975
2021 Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis. Nature communications 70 34099644
2007 Smad1 and Smad5 differentially regulate embryonic hematopoiesis. Blood 66 17761518
2016 miR-106b-5p and miR-17-5p suppress osteogenic differentiation by targeting Smad5 and inhibit bone formation. Experimental cell research 65 27426726
2002 Maternally supplied Smad5 is required for ventral specification in zebrafish embryos prior to zygotic Bmp signaling. Developmental biology 62 12376102
1999 Smad1 and Smad5 have distinct roles during dorsoventral patterning of the zebrafish embryo. Developmental dynamics : an official publication of the American Association of Anatomists 62 10590480
2013 Genistein promotion of osteogenic differentiation through BMP2/SMAD5/RUNX2 signaling. International journal of biological sciences 60 24339730
2009 Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors. Endocrinology 57 19819941
2002 Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis. Blood 52 12393578
2008 Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment. Development (Cambridge, England) 51 18448565
2017 Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis. Cell research 49 28675158
1999 Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome. Gut 49 10446110
2008 BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development. Developmental biology 48 18374325
2003 Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5. Endocrinology 48 12746314
2013 MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the noncanonical TGF-β1/SMAD5 signaling module. Blood 43 24136167
2009 Extramedullary erythropoiesis in the adult liver requires BMP-4/Smad5-dependent signaling. Experimental hematology 43 19375646
2004 Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. American journal of physiology. Lung cellular and molecular physiology 43 14711801
2017 miR-155 Inhibits Mouse Osteoblast Differentiation by Suppressing SMAD5 Expression. BioMed research international 42 28473977
2016 Inhibition of miR-222-3p activity promoted osteogenic differentiation of hBMSCs by regulating Smad5-RUNX2 signal axis. Biochemical and biophysical research communications 42 26809090
2019 Ablation of Hepatocyte Smad1, Smad5, and Smad8 Causes Severe Tissue Iron Loading and Liver Fibrosis in Mice. Hepatology (Baltimore, Md.) 41 31127639
1999 Characterization of zebrafish smad1, smad2 and smad5: the amino-terminus of smad1 and smad5 is required for specific function in the embryo. Mechanisms of development 41 10525190
2019 Long noncoding RNA SMAD5-AS1 acts as a microRNA-106a-5p sponge to promote epithelial mesenchymal transition in nasopharyngeal carcinoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 31557058
2021 Silencing of long non-coding RNA HCP5 inhibits proliferation, invasion, migration, and promotes apoptosis via regulation of miR-299-3p/SMAD5 axis in gastric cancer cells. Bioengineered 38 33371778
2002 Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. Blood cells, molecules & diseases 38 12064918
2021 Icariin regulates miR-23a-3p-mediated osteogenic differentiation of BMSCs via BMP-2/Smad5/Runx2 and WNT/β-catenin pathways in osteonecrosis of the femoral head. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 37 35002378
2019 Long non-coding RNA HOXA11-AS induces type I collagen synthesis to stimulate keloid formation via sponging miR-124-3p and activation of Smad5 signaling. American journal of physiology. Cell physiology 37 31411918
2007 Inactivation of Smad5 in endothelial cells and smooth muscle cells demonstrates that Smad5 is required for cardiac homeostasis. The American journal of pathology 36 17456754
2015 Effect of Anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP-15) on steroidogenesis in primary-cultured human luteinizing granulosa cells through Smad5 signalling. Journal of assisted reproduction and genetics 34 26003656
2014 A heterocyclic molecule kartogenin induces collagen synthesis of human dermal fibroblasts by activating the smad4/smad5 pathway. Biochemical and biophysical research communications 32 24928394
2006 Developmental pattern of expression of BMP receptors and Smads and activation of Smad1 and Smad5 by BMP9 in mouse basal forebrain. Brain research 32 16626664
2002 Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection. The Journal of biological chemistry 32 12473652
2019 Long noncoding RNA TUG1 inhibits osteogenesis of bone marrow mesenchymal stem cells via Smad5 after irradiation. Theranostics 31 31149038
2014 Transcriptional factors smad1 and smad9 act redundantly to mediate zebrafish ventral specification downstream of smad5. The Journal of biological chemistry 30 24488494
2006 Smad5 is dispensable for adult murine hematopoiesis. Blood 30 16896158
2013 c-Abl-dependent molecular circuitry involving Smad5 and phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2-induced osteogenesis. The Journal of biological chemistry 28 23821550
2001 Characterization of the DNA-binding property of Smad5. Biochemical and biophysical research communications 27 11527422
2018 MicroRNA-145 promotes esophageal cancer cells proliferation and metastasis by targeting SMAD5. Scandinavian journal of gastroenterology 26 29852786
2017 Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells. Oncotarget 26 29207686
2014 BMP-2 induction of Dlx3 expression is mediated by p38/Smad5 signaling pathway in osteoblastic MC3T3-E1 cells. Journal of cellular physiology 26 24647893
2002 Internal ribosome entry site-mediated translation of Smad5 in vivo: requirement for a nuclear event. Nucleic acids research 26 12087169
2021 CircRNA FAT1 Regulates Osteoblastic Differentiation of Periodontal Ligament Stem Cells via miR-4781-3p/SMAD5 Pathway. Stem cells international 25 35003269
2020 LINC01410 promotes cell proliferation and migration of cholangiocarcinoma through modulating miR-124-3p/SMAD5 axis. The journal of gene medicine 25 31951299
2019 MALAT1 functions as a competing endogenous RNA to regulate SMAD5 expression by acting as a sponge for miR-142-3p in hepatocellular carcinoma. Cell & bioscience 25 31168355
2016 MicroRNA-135b inhibits odontoblast-like differentiation of human dental pulp cells by regulating Smad5 and Smad4. International endodontic journal 25 27422404
1997 Smad5, a tumor suppressor candidate at 5q31.1, is hemizygously lost and not mutated in the retained allele in human leukemia cell line HL60. Leukemia 25 9264367
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2020 miR-130a promotes immature porcine Sertoli cell growth by activating SMAD5 through the TGF-β-PI3K/AKT signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 32918760
2019 Long noncoding RNA UCA1 promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells via miRNA-145-5p/SMAD5 and miRNA-124-3p/SMAD4 axis. Biochemical and biophysical research communications 24 31036320
2012 Antagonism of Nodal signaling by BMP/Smad5 prevents ectopic primitive streak formation in the mouse amnion. Development (Cambridge, England) 24 22912414
2000 Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia. Blood 24 10845932
2011 Loss of Smad5 leads to the disassembly of the apical junctional complex and increased susceptibility to experimental colitis. American journal of physiology. Gastrointestinal and liver physiology 23 21212325
2020 Long non-coding RNA LINC01116 accelerates the progression of keloid formation by regulating miR-203/SMAD5 axis. Burns : journal of the International Society for Burn Injuries 22 32883538
2020 KCNQ1OT1 regulates osteogenic differentiation of hBMSC by miR-320a/Smad5 axis. European review for medical and pharmacological sciences 21 32271402
2007 Molecular Interaction Between Smurfl WW2 Domain and PPXY Motifs of Smadl, Smad5, and Smad6-Modeling and Analysis. Journal of biomolecular structure & dynamics 21 22670624
2006 C-type natriuretic peptide enhances osteogenic protein-1-induced osteoblastic cell differentiation via Smad5 phosphorylation. Journal of cellular biochemistry 21 16187313
2001 Transforming growth factor beta signalling in vitro and in vivo: activin ligand-receptor interaction, Smad5 in vasculogenesis, and repression of target genes by the deltaEF1/ZEB-related SIP1 in the vertebrate embryo. Molecular and cellular endocrinology 21 11451567
2020 Maternal high protein-diet programs impairment of offspring's bone mass through miR-24-1-5p mediated targeting of SMAD5 in osteoblasts. Cellular and molecular life sciences : CMLS 20 32734584
2018 Amniotic ectoderm expansion in mouse occurs via distinct modes and requires SMAD5-mediated signalling. Development (Cambridge, England) 20 29884675
2007 An intronic sequence mutated in flexed-tail mice regulates splicing of Smad5. Mammalian genome : official journal of the International Mammalian Genome Society 20 18060457
2004 Smad5: signaling roles in hematopoiesis and osteogenesis. The international journal of biochemistry & cell biology 20 15061132
2021 Repair abilities of mouse autologous adipose-derived stem cells and ShakeGel™3D complex local injection with intrauterine adhesion by BMP7-Smad5 signaling pathway activation. Stem cell research & therapy 19 33736694
2015 Structural basis for the Smad5 MH1 domain to recognize different DNA sequences. Nucleic acids research 19 26304548
2021 miR-20a-5p contributes to osteogenic differentiation of human dental pulp stem cells by regulating BAMBI and activating the phosphorylation of Smad5 and p38. Stem cell research & therapy 18 34294156
2007 Molecular interaction between Smurf1 WW2 domain and PPXY motifs of Smad1, Smad5, and Smad6--modeling and analysis. Journal of biomolecular structure & dynamics 18 17676934
2006 Jun activation domain-binding protein 1 binds Smad5 and inhibits bone morphogenetic protein signaling. Arthritis and rheumatism 17 17133595
2016 MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5. Oncotarget 16 27438143
2013 Genetic polymorphism of SMAD5 is associated with Kawasaki disease. Pediatric cardiology 16 24163009
2012 Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death. Developmental biology 16 22240098
2019 MicroRNA-132-3p represses Smad5 in MC3T3-E1 osteoblastic cells under cyclic tensile stress. Molecular and cellular biochemistry 15 31004309
2017 Calcium Supplement Derived from Gallus gallus domesticus Promotes BMP-2/RUNX2/SMAD5 and Suppresses TRAP/RANK Expression through MAPK Signaling Activation. Nutrients 15 28513557
2015 TGFβ1a regulates zebrafish posterior lateral line formation via Smad5 mediated pathway. Journal of molecular cell biology 15 25603803
2014 Suppression of transforming growth factor β receptor 2 and Smad5 is associated with high levels of microRNA miR-155 in the oral mucosa during chronic simian immunodeficiency virus infection. Journal of virology 15 25540365
2010 Smad5 regulates Akt2 expression and insulin-induced glucose uptake in L6 myotubes. Molecular and cellular endocrinology 15 20079400
2005 Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes. Experimental cell research 15 15878335
2019 A New Insight of Kartogenin Induced the Mesenchymal Stem Cells (MSCs) Selectively Differentiate into Chondrocytes by Activating the Bone Morphogenetic Protein 7 (BMP-7)/Smad5 Pathway. Medical science monitor : international medical journal of experimental and clinical research 14 31271564
2014 Alk3/Alk3b and Smad5 mediate BMP signaling during lymphatic development in zebrafish. Molecules and cells 14 24608800