Affinage

SBF1

Myotubularin-related protein 5 · UniProt O95248

Length
1868 aa
Mass
208.4 kDa
Annotated
2026-06-10
29 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SBF1 (MTMR5) is a catalytically inactive pseudophosphatase of the myotubularin family that functions as a regulatory partner of active phosphoinositide phosphatases and a multidomain signaling protein governing tissue-specific differentiation programs (PMID:12668758, PMID:11994405, PMID:27335132). It interacts specifically with the active phosphatase MTMR2 — but not MTM1 — through reciprocal coiled-coil domains, and this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization (PMID:12668758). SBF1 lost catalytic activity through conserved substitutions in its phosphatase pocket, and was first identified through binding the SET domain of the proto-oncogene Hrx/MLL, a SET-interaction module sufficient to stimulate growth of primary B cell precursors (PMID:9689104). The full-length protein carries PH, GEF homology, and myotubularin homology domains, all required for its growth-inhibitory activity; removal of the N-terminal 44 residues converts it into a transforming protein and permits partial nuclear localization, whereas the endogenous protein is cytoplasmic (PMID:11686296). In vivo, SBF1 is essential for spermatogenesis: loss of function in mouse and rat produces azoospermia and male infertility, with the defect initiating at the pachytene-to-haploid spermatid transition (PMID:11994405, PMID:27335132). In peripheral nerve, SBF1 acts during myelination in a manner partly redundant with MTMR13, with its loss reducing the number of myelinated axons through radial sorting defects (PMID:34718573), and loss-of-function mutations in patients cause sensory-motor axonal neuropathy (CMT4B3) with necklace fibres (PMID:32444983). Patient fibroblasts reveal an uncoupling of selective mitophagy from macroautophagy upon SBF1 dysfunction (PMID:40998285).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 Medium

    Established SBF1's molecular identity as a catalytically dead myotubularin-family protein and linked it to chromatin/oncogene signaling by showing it binds the SET domain of MLL/Hrx.

    Evidence SET-domain binding assay and retroviral overexpression/deletion analysis in primary B cell precursors

    PMID:9689104

    Open questions at the time
    • Mechanism by which SET binding stimulates B cell precursor growth unresolved
    • Single lab, no in vivo validation of the MLL interaction
    • Did not define the phosphoinositide-related role of the pseudophosphatase domain
  2. 2001 Medium

    Defined the domain architecture and revealed an N-terminal autoinhibitory element that suppresses transformation and enforces cytoplasmic localization.

    Evidence Overexpression and deletion mutagenesis in NIH 3T3 cells with proliferation, transformation, and fractionation readouts

    PMID:11686296

    Open questions at the time
    • Physiological relevance of the transforming activity unestablished
    • No independent replication
    • Endogenous regulators of the N-terminal switch unknown
  3. 2002 High

    Demonstrated an essential, non-redundant in vivo role in spermatogenesis through a clean genetic knockout, placing the defect at a specific developmental transition.

    Evidence Sbf1 null mouse with histology, immunohistochemistry, and expression analysis

    PMID:11994405 PMID:27335132

    Open questions at the time
    • Molecular substrate/pathway driving the pachytene-to-spermatid block not defined
    • Whether Sertoli cell vacuolation is primary or secondary unresolved
  4. 2003 High

    Showed SBF1 is a regulatory subunit of an active phosphatase, explaining how a catalytically dead protein influences phosphoinositide metabolism.

    Evidence Reciprocal Co-IP with MS identification, coiled-coil domain mutagenesis, and in vitro enzymatic activity assay

    PMID:12668758

    Open questions at the time
    • Phosphoinositide species and cellular compartments controlled by the MTMR5-MTMR2 complex in vivo not mapped
    • Structural basis of activity enhancement undetermined
  5. 2016 Medium

    Confirmed the spermatogenesis requirement in an independent organism via a natural loss-of-function allele, strengthening the causal link.

    Evidence Genetic mapping, candidate sequencing, and protein-absence western blot in rat testis

    PMID:27335132

    Open questions at the time
    • Does not extend the mechanism beyond the mouse phenotype
    • Cellular target of the spermatogenic defect not addressed
  6. 2019 Medium

    Established SBF1 loss-of-function as a cause of human sensory-motor axonal neuropathy, connecting the gene to peripheral nerve disease.

    Evidence Whole-exome sequencing, cDNA analysis, and western blot of patient fibroblasts (single family)

    PMID:32444983

    Open questions at the time
    • Single family limits genotype-phenotype generalization
    • Cellular mechanism of axonal degeneration not addressed
  7. 2022 High

    Dissected SBF1's peripheral nerve function from its paralog MTMR13, revealing partial redundancy and a specific role in axon radial sorting.

    Evidence Single and double conditional knockout mice with nerve histology, protein quantification, and developmental expression profiling

    PMID:34718573

    Open questions at the time
    • Molecular basis of the radial sorting defect undefined
    • How MTMR2 stabilizes Mtmr5/Mtmr13 mechanistically unclear
  8. 2025 Medium

    Linked SBF1 dysfunction to a selective autophagy defect, showing macroautophagy and PINK1-PRKN mitophagy become uncoupled.

    Evidence LC3B/SQSTM1 flux, PINK1/PRKN recruitment, and aggregate staining in CMT4B3 patient fibroblasts (single lab, no genetic rescue)

    PMID:40998285

    Open questions at the time
    • No genetic rescue to confirm causality
    • Mechanistic link between SBF1 phosphoinositide regulation and autophagy uncoupling not established
    • Relevance to the in vivo neuropathy phenotype untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SBF1's phosphoinositide-regulatory role (via MTMR2) mechanistically connects to its disparate phenotypes — spermatogenesis, radial sorting, and autophagy uncoupling — remains unresolved.
  • No unifying substrate or pathway tying the molecular and organismal phenotypes together
  • Role of the MLL/SET interaction in nerve or testis biology unexplored
  • No structural model of the MTMR5-MTMR2 complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 1
Partners
MLLMTMR2

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 MTMR5/SBF1 (SBF1) specifically interacts with MTMR2 but not MTM1, via the coiled-coil domain of both proteins; mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. Co-immunoprecipitation, mass spectrometry identification, coiled-coil domain mutagenesis, enzymatic activity assay Proceedings of the National Academy of Sciences of the United States of America High 12668758
2001 Full-length SBF1 contains PH, GEF homology, and myotubularin homology domains. Forced expression in NIH 3T3 cells inhibits proliferation and alters morphology, requiring intact PH, GEF, and myotubularin homology domains. Deletion of the N-terminal 44 amino acids converts SBF1 from a growth inhibitor to a transforming protein. Oncogenic forms partially localize to the nucleus, whereas endogenous SBF1 is exclusively cytoplasmic. Overexpression/deletion mutagenesis in NIH 3T3 cells, subcellular fractionation/localization, proliferation and transformation assays Journal of cell science Medium 11686296
1998 SBF1 was originally discovered by its physical interaction with the SET domain of the proto-oncogene Hrx (MLL). SBF1 lacks phosphatase activity due to conserved amino acid changes in its catalytic pocket. The SET interaction domain of SBF1 is necessary and sufficient for growth stimulation of primary B cell precursors. Protein interaction assay (SET domain binding), retroviral overexpression in bone marrow cultures, structure/function deletion analysis Proceedings of the National Academy of Sciences of the United States of America Medium 9689104
2002 Sbf1 is a catalytically inactive pseudophosphatase expressed at high levels in seminiferous tubules (Sertoli cells, spermatogonia, pachytene spermatocytes). Mice nullizygous for Sbf1 exhibit male infertility with azoospermia; the spermatogenic defect initiates during the first wave of spermatogenesis at 17 days post-birth at the pachytene-to-haploid spermatid transition, with Sertoli cell vacuolation as the earliest phenotype. Sbf1 knockout mouse (null allele), histology, immunohistochemistry, expression analysis The Journal of clinical investigation High 11994405 27335132
2022 In mouse peripheral nervous system, Mtmr2 is required to maintain wild-type protein levels of Mtmr5 and Mtmr13, suggesting they function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 causes perinatal lethality, indicating partial redundancy. Loss of Mtmr5 alone does not cause CMT4B-like myelin outfoldings but results in fewer myelinated axons in adult nerves, likely due to axon radial sorting defects; Mtmr5 levels are highest during radial sorting and drop sharply after postnatal day 7. Double and single conditional knockout mice, nerve morphology/histology, western blot for protein levels, developmental expression profiling Human molecular genetics High 34718573
2016 A splicing mutation in rat Sbf1 (intron 37 splice site G>A) causes absence of full-length Sbf1 protein in the testis, resulting in azoospermia and male infertility as the sole phenotype, confirming a specific role for Sbf1 in spermatogenesis and corroborating results from the mouse knockout. Genetic mapping, candidate gene sequencing, western blot (protein absence in mutant testis), histology Reproduction (Cambridge, England) Medium 27335132
2025 In CMT4B3 patient-derived fibroblasts with compound heterozygous MTMR5/SBF1 mutations, basal macroautophagy is normal but fails to upregulate in response to mitochondrial stress or protein aggregates. Conversely, mitophagy via the PINK1-PRKN pathway is strongly activated, revealing an uncoupling between macroautophagy and mitophagy caused by MTMR5/SBF1 dysfunction. LC3B/SQSTM1 flux assay, PINK1/PRKN recruitment assay, mitophagosome/autolysosome quantification, Proteostat aggregate staining in patient fibroblasts Life sciences Medium 40998285
2019 A novel homozygous frameshift deletion in SBF1 exon 40 results in markedly reduced MTMR5 protein levels in patient fibroblasts, establishing that loss-of-function SBF1 mutations cause sensory-motor axonal neuropathy with necklace fibres on muscle biopsy. Whole-exome sequencing, cDNA analysis, western blot of patient fibroblasts Journal of neurology Medium 32444983

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. American journal of human genetics 232 12687498
2003 Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proceedings of the National Academy of Sciences of the United States of America 121 12668758
1991 Silencer region of a chalcone synthase promoter contains multiple binding sites for a factor, SBF-1, closely related to GT-1. Plant molecular biology 81 1893099
2002 Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1. The Journal of clinical investigation 61 11994405
2013 SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology 56 23749797
2014 SBF-1 exerts strong anticervical cancer effect through inducing endoplasmic reticulum stress-associated cell death via targeting sarco/endoplasmic reticulum Ca(2+)-ATPase 2. Cell death & disease 35 25522275
2001 Pseudo-phosphatase Sbf1 contains an N-terminal GEF homology domain that modulates its growth regulatory properties. Journal of cell science 29 11686296
1998 Growth stimulation of primary B cell precursors by the anti-phosphatase Sbf1. Proceedings of the National Academy of Sciences of the United States of America 28 9689104
2015 Blockade of the interaction between Bcr-Abl and PTB1B by small molecule SBF-1 to overcome imatinib-resistance of chronic myeloid leukemia cells. Cancer letters 19 26721204
2012 SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3. Biochemical pharmacology 19 22525724
2018 Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease. Clinical genetics 12 30039846
2016 SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement. Neurogenetics 12 28005197
2022 Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination. Human molecular genetics 10 34718573
2022 A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder. Scientific reports 10 36104480
2021 Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells. Investigational new drugs 8 33411211
2021 Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction. BMC medical genomics 8 34118926
2018 SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells. Journal of pharmacological sciences 8 30415825
2020 A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres. Journal of neurology 7 32444983
2014 DNA microarray reveals ZNF195 and SBF1 are potential biomarkers for gemcitabine sensitivity in head and neck squamous cell carcinoma cell lines. International journal of clinical and experimental pathology 7 24817947
2022 Generation and characterization of CSSi016-A (9938) human pluripotent stem cell line carrying two biallelic variants in MTMR5/SBF1 gene resulting in a case of severe CMT4B3. Stem cell research 4 36272304
2019 Discovery of SBF1 as an allosteric inhibitor targeting the PIF-pocket of 3-phosphoinositide-dependent protein kinase-1. Journal of molecular modeling 4 31197600
2016 Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat. Reproduction (Cambridge, England) 4 27335132
2025 Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3. Brain communications 2 40066109
2025 Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts. Life sciences 1 40998285
2024 Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene. Stem cell research 1 39461113
2019 SBF-1 inhibits contact hypersensitivity in mice through down-regulation of T-cell-mediated responses. BMC pharmacology & toxicology 1 31864413
2026 Pediatric toe-walking cohort with heterozygous SBF1 variants: A phenotypic description. Global medical genetics 0 41737274
2025 SBF-1 suppresses colorectal cancer cell growth via modulating cholesterol metabolic reprogramming. Biochemical and biophysical research communications 0 41317708
2024 A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3. Frontiers in neurology 0 39664754

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