SH3BP2 (
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of ph ...
-binding protein 2) is a protein that comes from a gene located on Chromosome 4. It is widely expressed in hematopoietic cells, including:
Macrophages
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
,
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.
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
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.
Mutated SH3BP2 can lead to upregulation of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha
(TNF-α), interleukin 1-beta (
IL-1β), and
RANKL
Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiat ...
, creating a positive feedback loop furthering osteoclast activation.
SH3BP2 role in Gastrointestinal Stromal Tumors
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
Platelet-derived growth factor receptor A, also termed CD140a, is a Receptor (biochemistry), receptor located on the surface of a wide range of cell types. The protein is encoded in the human by the ''PDGFRA'' gene. This receptor binds to certain ...
.
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. The silencing of the adaptor protein, SH3BP2, also indirectly downregulates ETV1 and MITF, through miRNA-mediated post-transcriptional repression.
References
See also
*
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of ph ...
External links
GeneReviews/NCBI/NIH/UW entry on Cherubism*
Genetics Home Reference on SH3BP2
{{Adaptor proteins