Alt. symbols: CIN85

Approved name: SH3 domain containing kinase binding protein 1
Alt. names: SH3 domaincontaining kinasebinding protein 1 | CD2binding protein 3 | SH3domain kinase binding protein 1 | Src family kinasebinding protein 1 | cCblinteracting protein | cblinteracting protein of 85 kDa | human Src family kinasebinding protein 1 | migrationinducing gene 18 | srcrelated kinase binding protein1

Location: Xp22.12: 19533977 - 19887600 (-)
Gene type: protein_coding, 50 transcripts.

Scores: LoFtool: 0.309000 | pLI: 0.99864313 | LOEUF: 0.194

HGNC: 13867

NCBI: 30011, RefSeq: NG_021367.1

Ensembl: ENSG00000147010.19

LRG_ | Status: none

OMIM: 300374

Expression | ProteinAtlas

SH3KBP1 encodes CIN85, an adapter protein involved in regulating diverse signal transduction pathways. It has been implicated in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through an association with ubiquitin ligase c-Cbl and endophilins (PMID: 12177062 , 15090612). It also promotes recycling of TGF-β receptors to the cell surface (PMID: 26169354) and regulates ligand-dependent endocytosis of the IgE receptor (PMID: 8382611). In B cells, CIN85 promotes Cbl-mediated regulation of BCR signaling (PMID: 22262777), including BCR-induced NF-κB activation in association with Syk substrate SLP65/BLNK (PMID: 21822214). This is achieved at least partly through effects on Ca2+ flux and diacylglycerol (DAG) production, which synergistically control the upstream NF-κB regulator PKC-β. In T cells, CIN85 is recruited to the TCR signaling complex after receptor ligation to negatively regulate T cell activation through its association with phosphatase Sts-2 (PMID: 30723173). In neutrophils, CIN85 translocates like c-Cbl from the cytosol to the plasma membrane upon receptor cross-linking (PMID: 21372129). The neutrophil FcγRIIa receptor plays a direct role in phagocytosis and CIN85 is thought to help attenuate its expression and function by c-Cbl-mediated proteasomal degradation in a PKC-dependent manner. In association with protein phosphatase 2A (PP2Ac), CIN85 has also been implicated in regulating integrin-dependent platelet function (PMID: 27334924). CIN85 is also thought to be involved in regulation of cell morphology, migration, and adhesion (PMID: 12771190, 17606992), as well as cellular stress responses via MAPK signaling (PMID: 16256071) and modulation of TNF-mediated apoptosis (PMID: 15707590).

Hemizygous SH3KBP1 mutation has been associated with an X-linked recessive primary immunodeficiency [OMIM: 300310] characterized by onset of recurrent infections in early childhood due to impaired antibody production. Keller et al. (2018) identified a 247.5 kb deletion encompassing exons 2 to 6 of SH3KBP1 in 2 brothers with recurrent infections and impaired antibody responses (PMID: 29636373). The proband was a 12-year-old boy with low serum IgM, IgG2, and IgG4 levels who experienced recurrent b acterial infections until age 4 years old, when his infection history apparently improved. He had normal levels of circulating B cells and subtypes, including transitional, naive, memory cells, and plasmablasts, although there were some subtle abnormalities. However, his IgG response to pneumococcal vaccination (polysaccharide) was insufficient, although responses to tetanus toxoid were normal. He had no abnormalities of T cell proliferation, activation, or intracellular signaling. His brother had had panhypogammaglobulinemia complicated by constant infections (i.e. sinusitis, otitis media, pneumonia) since early childhood; he died at age 15 years from a bacterial infection complicated by septic shock and multiorgan failure. In addition, both brothers had been diagnosed at age 11 with ADHD, mildly impaired adaptive skills, and obesity, reminiscent of the murine phenotypes related to CNS-specific CIN85 LOF (PMID: 20551902). Because T cells still showed robust TCR signaling and function in the absence of CIN85, the authors concluded that the antibody deficiencies seen in these patients was unlikely due to primary defects in T cell help for antigen-stimulated B cells, but more likely attributable to a B-cell intrinsic deficit of antigen reactivity. Indeed, Kometani et al. (2011) had shown that expression of a constitutively active version of IKK-β bypassed the need for canonical NF-κB activation in the conditional CIN85 mouse mutant, and corrected its defective antibody response to T cell-independent type II antigens (PMID: 21708930). [Load More]