SMA-2 is one of two receptor-regulated Smads (R-Smads, with SMA-3) in the C. elegans DBL-1/BMP-like Sma/Mab pathway. It is a dwarfin/MAD-family protein with an N-terminal MH1 DNA-binding domain and a C-terminal MH2 domain. Downstream of the DAF-4 type II and SMA-6 type I receptors, SMA-2 is thought to act with SMA-3 and the co-Smad SMA-4 as a heteromeric transcription factor. This complex controls postembryonic growth, so loss of sma-2 gives small animals with smaller cells but normal cell numbers. It also controls patterning of the male tail sensory rays and spicules, and it represses targets such as the CRISP-family gene lon-1. SMA-2 acts in the same cells as the receptor DAF-4. It modestly enhances SMA-3 function in male tail tip retraction, binds DAF-16/FOXO, and is needed for BMP-dependent M lineage fate in sma-9 mutants. The Sma/Mab pathway also limits reproductive span, and sma-2 mutants keep reproducing later in life, with young-looking, more fertilizable oocytes and better chromosome segregation fidelity, an effect that is noncell-autonomous and separable from the control of body size.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of RNA polymerase II cis-regulatory sequence-specific DNA binding from the Smad/MAD family node. The protein has an MH1 (MAD homology 1) DNA-binding domain and an MH2 domain, the typical Smad layout. Reason: Smad MH1 domains bind DNA directly, and this function is ancestral across the Smad family; nothing suggests it has been lost in this worm Smad. Direct DNA binding by the worm protein has not been shown biochemically, but the PAINT node placement is sound. The module models this protein as a nuclear Smad transcription factor. Supporting Evidence: PMID:8570636 These analyses suggest that dwarfins are conserved cytoplasmic signal transducers. PMID:28549065 The BMP signaling cascade involves extracellular ligands like DBL-1, type I (SMA-6) and type II (DAF-4) receptors, R-Smads (SMA-2 and SMA-3), a co-Smad (SMA-4), and a transcription co-factor (SMA-9) [13β15]. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of DNA-binding transcription factor activity, RNA polymerase II-specific, from the Smad family node. Reason: Smads are signal-activated transcription factors that are phosphorylated by receptors and then move into the nucleus. This is the core molecular function of the Smads in the DBL-1/BMP-like (Sma/Mab) pathway, and it matches the module's modelling of the Smad step. Supporting Evidence: PMID:8570636 These analyses suggest that dwarfins are conserved cytoplasmic signal transducers. PMID:28549065 The BMP signaling cascade involves extracellular ligands like DBL-1, type I (SMA-6) and type II (DAF-4) receptors, R-Smads (SMA-2 and SMA-3), a co-Smad (SMA-4), and a transcription co-factor (SMA-9) [13β15]. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleus, from the UniProt subcellular location mapping. Reason: Smads act in the nucleus as transcription factors. Nuclear localization of the paralog SMA-3 is directly shown (PMID:12397107). Supporting Evidence: PMID:12397107 SMA-3::GFP is nuclear localized in all of these tissues, and that nuclear localization is enhanced by SMA-6 activity |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000002 | ACCEPT | Summary: Transcription regulator complex, from an InterPro2GO mapping of the Smad domains. Reason: This is consistent with Smads acting in transcription-regulatory complexes. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm, from the UniProt subcellular location mapping. Reason: Inactive Smads are cytoplasmic and are recruited to receptors. This is consistent with the dwarfin description as cytoplasmic signal transducers. Supporting Evidence: PMID:8570636 These analyses suggest that dwarfins are conserved cytoplasmic signal transducers. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Regulation of DNA-templated transcription, from an InterPro2GO mapping. Reason: This is a correct but general parent of the IBA RNA polymerase II term. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: regulation of transcription by RNA polymerase II. Reason: This is the general process carried out by a Smad transcription factor. It is consistent with the pathway regulating target genes such as lon-1. Supporting Evidence: PMID:12051826 This provides evidence that lon-1 is negatively regulated by Sma/Mab pathway signaling. |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: anatomical structure morphogenesis, a very broad developmental term transferred across the Smad family. Reason: Sma/Mab Smads do act in morphogenesis (for example male tail rays and spicules), but this broad term adds little. It is kept as non-core. Supporting Evidence: PMID:12717735 DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads |
| GO:0009791 post-embryonic development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA: post-embryonic development. Reason: This is true in a broad sense, since the Smads drive postembryonic growth, but it is very general. Kept as non-core. Supporting Evidence: PMID:12397107 results in viable, but smaller animals because of a reduction in postembryonic growth |
| GO:0009791 post-embryonic development | IGI PMID:17535251 Mutants carrying two sma mutations are super small in the ne... | KEEP AS NON CORE | Summary: Post-embryonic development, from a sma-5 double-mutant (IGI) analysis. Reason: The sma-5; sma-2 doubles are much smaller than either single mutant, so sma-2 acts in postembryonic growth in parallel to SMA-5. The more specific growth term captures this better. Kept as non-core. Supporting Evidence: PMID:17535251 indicating that the sma-5 gene functions independently of the DBL-1/TGFbeta pathway |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: cell differentiation, a broad term. Reason: Smads regulate cell fate in some contexts (for example M lineage fate in sma-9 mutants), but generic cell differentiation is not a core descriptor for this gene. Kept as non-core. Supporting Evidence: PMID:25978409 Mutations in the Sma/Mab pathway fully restore the sma-9(0) M lineage phenotype back to that of wild-type animals |
| GO:0030307 positive regulation of cell growth | IGI PMID:17535251 Mutants carrying two sma mutations are super small in the ne... | KEEP AS NON CORE | Summary: Positive regulation of cell growth (IGI with sma-5). Reason: sma double mutants are tiny but have normal cell numbers, so the size reduction is due to smaller cells. Cell growth is a real component of Smad-driven body growth, but it is secondary to organismal growth. Supporting Evidence: PMID:17535251 But the numbers of cells are not changed, suggesting that the cells are very small. |
| GO:0030307 positive regulation of cell growth | IMP PMID:17535251 Mutants carrying two sma mutations are super small in the ne... | KEEP AS NON CORE | Summary: Positive regulation of cell growth (IMP). Reason: This is supported by the observation that small body size reflects small cells, not fewer cells. Non-core relative to body-size control. Supporting Evidence: PMID:17535251 But the numbers of cells are not changed, suggesting that the cells are very small. |
| GO:0030509 BMP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: BMP signaling pathway. Reason: DBL-1 is a BMP-related ligand. It signals through DAF-4/SMA-6 receptors to the SMA-2/SMA-3/SMA-4 Smads, which are core intracellular transducers of this pathway. Supporting Evidence: PMID:28549065 The BMP signaling cascade involves extracellular ligands like DBL-1, type I (SMA-6) and type II (DAF-4) receptors, R-Smads (SMA-2 and SMA-3), a co-Smad (SMA-4), and a transcription co-factor (SMA-9) [13β15]. PMID:12717735 DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads |
| GO:0040018 positive regulation of multicellular organism growth | IGI PMID:12051826 lon-1 regulates Caenorhabditis elegans body size downstream ... | ACCEPT | Summary: Positive regulation of body growth, from epistasis with lon-1 (IGI). Reason: Loss of DBL-1 pathway Smads reduces postembryonic growth, giving small (Sma) animals. This is the defining output of the Sma/Mab pathway and the core biological role of the Smads. lon-1 acts downstream and is repressed by the pathway. Supporting Evidence: PMID:12051826 lon-1 lies downstream of the Sma/Mab signaling cascade |
| GO:0040018 positive regulation of multicellular organism growth | IGI PMID:17535251 Mutants carrying two sma mutations are super small in the ne... | ACCEPT | Summary: Positive regulation of body growth, from sma-5 double mutants (IGI). Reason: Loss of DBL-1 pathway Smads reduces postembryonic growth, giving small (Sma) animals. This is the defining output of the Sma/Mab pathway and the core biological role of the Smads. Supporting Evidence: PMID:17535251 indicating that the sma-5 gene functions independently of the DBL-1/TGFbeta pathway |
| GO:0040018 positive regulation of multicellular organism growth | IMP PMID:12717735 Genetic screen for small body size mutants in C. elegans rev... | ACCEPT | Summary: Positive regulation of multicellular organism growth (body size). Reason: Loss of DBL-1 pathway Smads reduces postembryonic growth, giving small (Sma) animals. This is the defining output of the Sma/Mab pathway and the core biological role of the Smads. Supporting Evidence: PMID:12717735 DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads PMID:12397107 results in viable, but smaller animals because of a reduction in postembryonic growth |
| GO:0040018 positive regulation of multicellular organism growth | IMP PMID:17535251 Mutants carrying two sma mutations are super small in the ne... | ACCEPT | Summary: Positive regulation of body growth (IMP). Reason: Loss of DBL-1 pathway Smads reduces postembryonic growth, giving small (Sma) animals. This is the defining output of the Sma/Mab pathway and the core biological role of the Smads. Supporting Evidence: PMID:17535251 But the numbers of cells are not changed, suggesting that the cells are very small. |
| GO:0042661 regulation of mesodermal cell fate specification | IGI PMID:25978409 Promotion of bone morphogenetic protein signaling by tetrasp... | KEEP AS NON CORE | Summary: Regulation of mesodermal cell fate specification (IGI with sma-9). Reason: Loss of Sma/Mab pathway components, including the Smads, fully suppresses the M lineage dorsal-to-ventral fate transformation of sma-9 mutants. So the Smads carry the BMP signal that drives the ventral (SM) fate in the M lineage, and SMA-9 antagonizes this signal on the dorsal side. This is a genuine but context-specific output, revealed mainly in sensitized backgrounds. Supporting Evidence: PMID:25978409 Mutations in the Sma/Mab pathway fully restore the sma-9(0) M lineage phenotype back to that of wild-type animals |
| GO:0045138 nematode male tail tip morphogenesis | IMP PMID:12717735 Genetic screen for small body size mutants in C. elegans rev... | ACCEPT | Summary: Nematode male tail tip morphogenesis (IMP). Reason: The male tail defect (Mab) is one of the two defining phenotypes of Sma/Mab pathway mutants. Supporting Evidence: PMID:12717735 DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads PMID:28068334 Loss-of-function mutations in any of these core members will result in a small body size, male tail sensory ray formation defects [17], reduced expression of the RAD-SMAD reporter [18], and suppression of the sma-9(cc604) M lineage defect [19]. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA: regulation of developmental process. Reason: Broad parent term. It is correct but uninformative. |
| GO:0051239 regulation of multicellular organismal process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA: regulation of multicellular organismal process. Reason: Broad parent of body-size regulation. It is correct but uninformative. |
| GO:0060395 SMAD protein signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: SMAD protein signal transduction. Reason: This is the defining process for a Smad: a receptor-regulated or co-Smad that carries the signal from the receptor to the nucleus. Supporting Evidence: PMID:8570636 These analyses suggest that dwarfins are conserved cytoplasmic signal transducers. PMID:28549065 The BMP signaling cascade involves extracellular ligands like DBL-1, type I (SMA-6) and type II (DAF-4) receptors, R-Smads (SMA-2 and SMA-3), a co-Smad (SMA-4), and a transcription co-factor (SMA-9) [13β15]. |
| GO:0070411 I-SMAD binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA: I-SMAD binding, transferred from vertebrate Smads that bind SMAD6/SMAD7. Reason: The C. elegans members of PANTHER PTHR13703 are sma-2, sma-3, sma-4, daf-3, daf-8 and daf-14. None falls in the inhibitory-Smad subfamilies (SMAD6 PTHR13703:SF28, SMAD7 PTHR13703:SF44), and no I-Smad partner has been characterized in this pathway. The binding capacity may be ancestral, but in C. elegans it has no known partner, so the term overstates what is known for this gene. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000344419 SUPPORTS SOURCE BUT NOT TARGET Smad family node seeded by vertebrate R-Smad/I-Smad interaction data (e.g. SMAD6/SMAD7 partners). In C. elegans, no PTHR13703 member falls in the I-Smad subfamilies, so the binding partner is not known in this lineage. |
| GO:0071144 heteromeric SMAD protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: heteromeric SMAD protein complex. Reason: R-Smad/co-Smad heteromers are the canonical active form. Genetically, SMA-2, SMA-3 and SMA-4 are all required for, and non-redundant in, the same pathway, which is consistent with a heteromeric complex. Note that a direct SMA-2/SMA-3 interaction was not detected by yeast two-hybrid (PMID:28549065), so the exact stoichiometry is unresolved. Supporting Evidence: PMID:9847239 indicating that they function in a common signaling pathway PMID:28549065 Even though it has been suggested previously that SMA-2 and SMA-3 form a heterodimer [41], we were unable to detect a direct interaction between SMA-2 and SMA-3 in this assay (S5 Fig). |
| GO:0090597 nematode male tail mating organ morphogenesis | IMP PMID:1782863 Pattern formation in the nematode epidermis: determination o... | ACCEPT | Summary: Nematode male tail mating organ morphogenesis (IMP), from the early male tail ray-patterning study. Reason: Sma/Mab Smad mutants have fused or abnormal rays and crumpled spicules. Male tail patterning is a core output of the pathway. Supporting Evidence: PMID:1782863 Mutations are described in six genes that alter the adult arrangement of the rays, frequently resulting in fusion of rays. PMID:28068334 Loss-of-function mutations in any of these core members will result in a small body size, male tail sensory ray formation defects [17], reduced expression of the RAD-SMAD reporter [18], and suppression of the sma-9(cc604) M lineage defect [19]. |
| GO:0110039 positive regulation of nematode male tail tip morphogenesis | IMP PMID:21408209 A bow-tie genetic architecture for morphogenesis suggested b... | KEEP AS NON CORE | Summary: Positive regulation of male tail tip morphogenesis (IMP), from the genome-wide tail tip RNAi screen. Reason: sma-2 RNAi alone had little effect but enhanced the Lep (retained larval tail tip) phenotype of sma-3(e491). This shows a modest, partly redundant contribution of SMA-2 to tail tip retraction. Supporting Evidence: PMID:21408209 Of the other known components of the TGF-Ξ² pathway, only sma-2 showed any RNAi phenotype: RNAi against sma-2 significantly enhanced the penetrance of the Lep phenotype of sma-3(e491) |
| GO:0160094 nematode pharynx development | IMP PMID:21868609 Cell architecture: surrounding muscle cells shape gland cell... | MODIFY | Summary: Nematode pharynx development (IMP), from pharynx length measurements. Reason: sma-2 mutants have a shorter pharynx but normal pharyngeal morphology. The defect is reduced postembryonic growth, not a defect in pharynx development as such, so an organ-growth term describes it better. Proposed replacements: positive regulation of organ growth Supporting Evidence: PMID:21868609 Unlike sma-1 mutants, sma-2 and sma-3 mutants undergo normal elongation and have normal pharyngeal morphology, but are smaller than wild type due to reduced postembryonic growth of cells. |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA: animal gross anatomical part developmental process. Reason: Broad term. It is correct but uninformative. |
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Download this section (compressed HTML)Q: Do SMA-2 and SMA-3 form an obligate heterotrimer with SMA-4 in vivo, given that no direct SMA-2/SMA-3 interaction was detected in yeast two-hybrid?
Q: Why does sma-2 make only a minor contribution to male tail tip retraction compared with sma-3?
Experiment: Co-immunoprecipitation of endogenously tagged SMA-2, SMA-3 and SMA-4 from hypodermal extracts, with and without DBL-1 overexpression, to define the active Smad complex.
Experiment: ChIP-seq of tagged SMA-2 to test whether it co-occupies SMA-3 target sites such as the lon-1 regulatory region.
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