SH3BP2
| SH3-domain binding protein 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | SH3BP2 | ||||||
| NCBI gene | 6452 | ||||||
| HGNC | 10825 | ||||||
| OMIM | 602104 | ||||||
| RefSeq | NM_003023 | ||||||
| UniProt | P78314 | ||||||
| Other data | |||||||
| Locus | Chr. 4 p16.3 | ||||||
| |||||||
SH3BP2 (SH3 domain-binding protein 2) is a protein that comes from a gene located on Chromosome 4. It is widely expressed in hematopoietic cells, including: Macrophages, B and T lymphocytes, and osteoclast precursors. SH3BP2 has an N-terminal pleckstrin homology domain to bind differentially to the SH3 domains of certain proteins of signal transduction pathways, as well as a proline-rich domain and a C-terminal Src homology domain.[1] It functions as an adaptor protein involved in signaling pathways, in concert with SRC kinases, SYK, and PLCγ, affecting immune cell activation, inflammatory signaling, and bone metabolism-- it is also associated with cherubism. It binds to phosphatidylinositol, linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation-dependent mechanism.
SH3BP2 Role in Osteoclast Genesis
[edit]A gain-of-function mutation in the protein's exon 9 region leads to several common mutations that affect its proline-rich domain, resulting in its hyperactivation. This upregulation of SH3BP2 increases osteoclast formation and activity, causing bone reabsorption and cyst-like lesions in a TNF-α-dependent mechanism. [2]
Mutated SH3BP2 can lead to upregulation of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and RANKL, creating a positive feedback loop furthering osteoclast activation. [1]
SH3BP2 role in Gastrointestinal Stromal Tumors
[edit]SH3BP2 is a key regulator in the growth and survival of gastrointestinal stromal tumors. It supports the expression of two transcriptional factors, ETV1 and MITF, and receptor kinases, KIT and PDGFRA.
There are certain therapies for GISTs that involve silencing SH3BP2 to reduce the expression of the receptor kinases KIT and PDGFRA, which are commonly mutated and drive GISTs development.[3] The silencing of the adaptor protein, SH3BP2, also indirectly downregulates ETV1 and MITF, through miRNA-mediated post-transcriptional repression.[4]
References
[edit]- ^ a b Reichenberger, Ernst J.; Levine, Michael A.; Olsen, Bjorn R.; Papadaki, Maria E.; Lietman, Steven A. (2012-05-24). "The role of SH3BP2 in the pathophysiology of cherubism". Orphanet Journal of Rare Diseases. 7 (1): S5. doi:10.1186/1750-1172-7-S1-S5. ISSN 1750-1172. PMC 3359958. PMID 22640988.
- ^ Mukai, Tomoyuki; Ishida, Shu; Ishikawa, Remi; Yoshitaka, Teruhito; Kittaka, Mizuho; Gallant, Richard; Lin, Yi-Ling; Rottapel, Robert; Brotto, Marco; Reichenberger, Ernst J; Ueki, Yasuyoshi (2014-12-01). "SH3BP2 Cherubism Mutation Potentiates TNF-α–Induced Osteoclastogenesis via NFATc1 and TNF-α–Mediated Inflammatory Bone Loss". Journal of Bone and Mineral Research. 29 (12): 2618–2635. doi:10.1002/jbmr.2295. ISSN 0884-0431. PMC 4262741. PMID 24916406.
- ^ Serrano-Candelas, Eva; Ainsua-Enrich, Erola; Navinés-Ferrer, Arnau; Rodrigues, Paulo; García-Valverde, Alfonso; Bazzocco, Sarah; Macaya, Irati; Arribas, Joaquín; Serrano, César; Sayós, Joan; Arango, Diego; Martin, Margarita (2018). "Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth". Molecular Oncology. 12 (8): 1383–1397. doi:10.1002/1878-0261.12332. ISSN 1878-0261. PMC 6068349. PMID 29885053.
- ^ Proaño-Pérez, Elizabeth; Serrano-Candelas, Eva; Mancia, Cindy; Navinés-Ferrer, Arnau; Guerrero, Mario; Martin, Margarita (2022-12-15). "SH3BP2 Silencing Increases miRNAs Targeting ETV1 and Microphthalmia-Associated Transcription Factor, Decreasing the Proliferation of Gastrointestinal Stromal Tumors". Cancers. 14 (24): 6198. doi:10.3390/cancers14246198. ISSN 2072-6694. PMC 9777313. PMID 36551682.
See also
[edit]External links
[edit]- GeneReviews/NCBI/NIH/UW entry on Cherubism
- SH3BP2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Genetics Home Reference on SH3BP2
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