Alternative titles; symbols
HGNC Approved Gene Symbol: SH3GL2
Cytogenetic location: 9p22.2 Genomic coordinates (GRCh38): 9:17,579,066-17,797,124 (from NCBI)
The Src homology-3 (SH3) domain is an evolutionarily conserved 50- to 60-amino acid module carried by intracellular proteins involved in the transduction of signals for cell polarization, motility, enzymatic activation, and transcriptional regulation. The SH3 domain drives protein-protein interactions through binding to proline-rich ligands. This binding function of the SH3 domain relies on its conserved secondary structure, whereas the primary structure of the SH3 domain is highly diverse. By PCR using degenerate oligonucleotides based on conserved regions of the SH3 domain, Giachino et al. (1997) identified cDNAs encoding a family of SH3 domain-containing proteins, including SH3GL1 (601768), SH3GL2, and SH3GL3 (603362). The predicted 352-amino acid SH3GL2 protein contains a C-terminal SH3 domain, which shares 92% and 84% amino acid sequence homology with the SH3 domains of SH3GL3 and SH3GL1, respectively. The SH3 domains of these proteins also show high homology to the C-terminal SH3 domain of GRB2 (108355). The N-terminal domains of SH3GL1, SH3GL2, and SH3GL3 are homologous to each other, but not to other known proteins, and are separated from the SH3 domain by a less conserved hinge segment. SH3GL1, SH3GL2, and SH3GL3 all contain a putative nuclear localization signal, potential tyrosine phosphorylation sites, and putative SH2-, SH3-, and PTB-binding sites. Northern blot analysis of several human tissues detected a 2.7-kb SH3GL2 transcript that was predominantly expressed in brain. A comparison between the brain and cerebellum of a 20-week-old fetus showed that SH3GL2 was expressed at higher levels in fetal cerebellum. SH3GL2 was highly expressed in adult frontal cortex.
Howard et al. (1999) demonstrated that endophilin-1 and SNX9 (605952) interact with the cytoplasmic domains of the metalloprotease disintegrins ADAM9 (602713) and ADAM15 (605548).
Endophilin-1 is a presynaptic protein that binds to dynamin (see 602377), a GTPase that is implicated in endocytosis and recycling of synaptic vesicles. Schmidt et al. (1999) showed that endophilin-1 is essential for the formation of synaptic-like microvesicles from the plasma membrane. They concluded that endophilin-1 may induce negative membrane curvature by converting an inverted cone-shaped lipid to a cone-shaped lipid in the cytoplasmic leaflet of the bilayer. Schmidt et al. (1999) proposed that through this action, endophilin-1 works with dynamin to mediate synaptic vesicle invagination from the plasma membrane and fission.
By screening with C-terminal CIN85 (300374) as bait, Soubeyran et al. (2002) identified endophilins A1, A2 (601768), and A3 as constitutive interactors, via their SH3 domains, with proline-rich sequences of CIN85. EGF (131530) stimulation results in a complex of CBL, CIN85, endophilins, and EGF receptors. Confocal microscopy demonstrated a diffuse cytoplasmic distribution in resting cells and a colocalization with EGF receptors in endocytic vesicles after EGF stimulation. Analysis with dominant interfering forms of CIN85 suggested that CIN85 is dispensable for polyubiquitination of EGF receptors but that it may be critical for the regulation of receptor endocytosis and lysosomal degradation. Soubeyran et al. (2002) concluded that CIN85 has a role in the control of postmembrane events such as targeting receptors for degradation and regulation of gene transcription, possibly by binding to multiple adaptor proteins.
Gallop et al. (2005) showed that the LPAAT activity associated with endophilin (Schmidt et al., 1999) is a contaminant of the purification procedure and could also be found associated with the pleckstrin homology domain of dynamin. Likewise, the LPAAT associated with CtBP/BARS (602618) is a copurification artifact. The proposed locus of activity in endophilins includes the BAR domain, which has no catalytic site but instead senses positive membrane curvature. Gallop et al. (2005) suggested that their data will prompt a reevaluation of the molecular details of membrane budding.
Using a protein pull-down strategy, Trempe et al. (2009) found that the ubiquitin-like (UBL) domain of parkin (PARK2; 602544) bound endophilins A1, A2, and A3 in mouse brain lysates. Binding was mediated by the SH3 domain of endophilin A1 and a highly conserved C-terminal motif (PxRK) of the parkin UBL domain. The parkin UBL domain bound the SH3 domains of several other BAR domain-containing proteins involved in vesicle trafficking, but it did not bind the SH3 domains of proteins lacking a BAR domain. Biochemical analysis revealed that the flexible C-terminal tail of the parkin UBL domain became structured upon binding the SH3 domain of endophilin A1. Phosphorylation promoted the interaction between endogenous parkin and endophilin A1 in mouse brain synaptosomes, which in turn led to increased levels of ubiquitinated synaptic proteins in wildtype mice, but not in parkin-knockout mice. Trempe et al. (2009) concluded that BAR-SH3 proteins, like the endophilins, are involved in parkin-mediated synaptic ubiquitination.
Using a panel of somatic cell hybrids, Giachino et al. (1997) mapped the SH3GL2 gene to chromosome 9. By FISH, they localized the gene to 9p22.
Gallop, J. L., Butler, P. J. G., McMahon, H. T. Endophilin and CtBP/BARS are not acyl transferases in endocytosis or Golgi fission. Nature 438: 675-678, 2005. [PubMed: 16319893] [Full Text: https://doi.org/10.1038/nature04136]
Giachino, C., Lantelme, E., Lanzetti, L., Saccone, S., Della Valle, G., Migone, N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Genomics 41: 427-434, 1997. [PubMed: 9169142] [Full Text: https://doi.org/10.1006/geno.1997.4645]
Howard, L., Nelson, K. K., Maciewicz, R. A., Blobel, C. P. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J. Biol. Chem. 274: 31693-31699, 1999. [PubMed: 10531379] [Full Text: https://doi.org/10.1074/jbc.274.44.31693]
Schmidt, A., Wolde, M., Thiele, C., Fest, W., Kratzin, H., Podtelejnikov, A. V., Witke, W., Huttner, W. B., Soling, H.-D. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 401: 133-141, 1999. [PubMed: 10490020] [Full Text: https://doi.org/10.1038/43613]
Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W. Y., Dikic, I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 416: 183-187, 2002. Note: Erratum: Nature 417: 102 only, 2002. [PubMed: 11894095] [Full Text: https://doi.org/10.1038/416183a]
Trempe, J.-F., Chen, C. X.-Q., Grenier, K., Camacho, E. M., Kozlov, G., McPherson, P. S., Gehring, K., Fon, E. A. SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination. Molec. Cell 36: 1034-1047, 2009. [PubMed: 20064468] [Full Text: https://doi.org/10.1016/j.molcel.2009.11.021]