Fragile Bones Secondary to SMURF1 Gene Duplication

Al-Rawi, Rawan; Al-Beshri, Ali; Mikhail, Fady M.; McCormick, Kenneth

doi:10.1007/s00223-020-00668-5

Cited by 5 publications

(8 citation statements)

References 12 publications

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“…In bone metabolism, SMURF1 inhibits R-Smad/Co-Smad complex nuclear translocation and directly ubiquitylates and degrades RUNX2, leading to suppression of osteoblastogenesis. Additionally, SMURF1 ubiquitylates and regulates MEKK2, resulting in inhibition of JNK activation and subsequent suppression of osteoblast activity and response to BMPs (28,30). Consistent with these molecular mechanisms, clinical features in the reported child with osteoporosis and bone fractures showed phenotypic similarity to those observed in mice with Smurf1 mutations.…”

Section: Hect-domain E3-ubiquitin Ligases and Human Disordersmentioning

confidence: 54%

“…A number of in vivo and in vitro studies have shown associations of SMURF1 (Smad Ubiquitin Regulatory Factor-1) with osteoblast function and response to BMPs (bone morphogenetic proteins) (27,28), and genetic variants in the genes encoding SMURF1-related proteins have been implicated in the risk of osteoporosis by hypothesis-free GWAS (29). Al−Rawi et al reported the first case of a microduplication in the SMURF1 gene in a 10-year-old girl suffering from two leg fractures with osteoporosis, severe developmental delay, infantile seizures and Bcell lymphoma (30). During the process of osteoblastogenesis, BMPs bind to homomeric type II receptor, which phosphorylates a glycine-serine-rich domain in homomeric type I receptor, leading to induction of signal transduction.…”

Section: Hect-domain E3-ubiquitin Ligases and Human Disordersmentioning

confidence: 99%

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E3-ubiquitin ligases and recent progress in osteoimmunology

Asano

Matsumoto²,

Wada³

et al. 2023

Front. Immunol.

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Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies.

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Section: Hect-domain E3-ubiquitin Ligases and Human Disordersmentioning

confidence: 54%

Section: Hect-domain E3-ubiquitin Ligases and Human Disordersmentioning

confidence: 99%

E3-ubiquitin ligases and recent progress in osteoimmunology

Asano

Matsumoto²,

Wada³

et al. 2023

Front. Immunol.

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“…Furthermore, it has been demonstrated that ALK5, a member of the KLF family, exerts an inhibitory effect on the restoration of neurological function. 116 Su et al 117 have shown that trimethylamine N-oxide (TMAO) exacerbates neurological damage through the SMURF2/ALK5 axis in a rat model of middle cerebral artery occlusion/reperfusion. During this process, SMURF2 enhances the ubiquitination and degradation of ALK5, inhibiting astrocyte proliferation, migration, and viability, ultimately mitigating neurological damage following ischemic stroke.…”

Section: Ischemic Strokementioning

confidence: 99%

“…Furthermore, Yamashita et al 138 discovered that SMURF1 can interact with SMAD6, resulting in the ubiquitin‐dependent degradation of BMP receptors and R‐SMADs, which synergistically enhances the inhibitory effect of SMAD6 on bone formation. In recent research, Rawan et al 116 have recently conducted research indicating that a 10‐year‐old girl is afflicted with osteoporosis as a result of a microduplication involving the SMURF1 gene. This conclusion is supported by the symptoms observed in SMURF1‐deficient mice, which demonstrate an increase in cortical bone and bone density over time 139 .…”

Section: Skeletal Diseasesmentioning

confidence: 99%

The role ofSMURFsin non‐cancerous diseases

et al. 2023

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The ubiquitin‐proteasome system is a crucial mechanism for regulating protein levels in cells, with substrate‐specific E3 ubiquitin ligases serving as an integral component of this system. Among these ligases are SMAD‐specific E3 ubiquitin‐protein ligase 1 (SMURF1) and SMAD‐specific E3 ubiquitin‐protein ligase 2 (SMURF2), which belong to the neural precursor cell‐expressed developmentally downregulated 4 (NEDD4) subfamily of Homologous to E6‐AP COOH terminus (HECT)‐type E3 ligases. As E3 ligases, SMURFs have critical functions in regulating the stability of multiple proteins, thereby maintaining physiological processes such as cell migration, proliferation, and apoptosis. The occurrence of many diseases is attributed to abnormal cell physiology and an imbalance in cell homeostasis. It is noteworthy that SMURFs play pivotal roles in disease progression, with the regulatory functions being complex and either facilitative or inhibitory. In this review, we elucidate the mechanisms by which SMURF1 and SMURF2 can regulate disease progression in non‐cancerous diseases. These significant findings offer potential novel therapeutic targets for various diseases and new avenues for research on SMURF proteins.

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“…Furthermore, Smurf1 −/− mice developed a notable phenotype, an age-dependent increase in bone mass, and osteoblasts with mutant Smurf1 markedly enhanced osteoblast differentiation [ 27 ]. Furthermore, a clinical case recently linked osteoporosis with a Smurf1 gene mutation, in which a 10-year-old girl was diagnosed with fractures and low bone mineral density, and a pathogenic microduplication involving the Smurf1 gene was detected by array comparative genomic hybridization [ 28 ]. More importantly, these clinical features are congruous with the phenotype of excess Smurf1 mutations in mice, which provides strong evidence for the use of transgenic mice as models for deep investigation.…”

Section: Nedd4 E3 Ligases and Bonementioning

confidence: 99%

NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

Chu

Liu

et al. 2022

IJMS

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Protein ubiquitination is a precisely controlled enzymatic cascade reaction belonging to the post-translational modification of proteins. In this process, E3 ligases catalyze the binding of ubiquitin (Ub) to protein substrates and define specificity. The neuronally expressed developmentally down-regulated 4 (NEDD4) subfamily, belonging to the homology to E6APC terminus (HECT) class of E3 ligases, has recently emerged as an essential determinant of multiple cellular processes in different tissues, including bone and tooth. Here, we place special emphasis on the regulatory role of the NEDD4 subfamily in the molecular and cell biology of osteogenesis. We elucidate in detail the specific roles, downstream substrates, and upstream regulatory mechanisms of the NEDD4 subfamily. Further, we provide an overview of the involvement of E3 ligases and deubiquitinases in the development, repair, and regeneration of another mineralized tissue—tooth.

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Fragile Bones Secondary to SMURF1 Gene Duplication

Cited by 5 publications

References 12 publications

E3-ubiquitin ligases and recent progress in osteoimmunology

E3-ubiquitin ligases and recent progress in osteoimmunology

The role ofSMURFsin non‐cancerous diseases

NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

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