HGNC Approved Gene Symbol: PACSIN2
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:42,869,766-43,015,149 (from NCBI)
Proteins containing a BIN (see 601248)/amphiphysin (AMPH; 600418)/Rvs167 (BAR) domain, such as PACSIN2, regulate membrane curvature. The positively charged surface of the BAR domain binds to the negatively charged inner surface of the plasma membrane, thereby bending the membrane according to the protein structure (Senju et al., 2011).
PACSIN family members, such as mouse Pacsin1 and chicken FAP52, are cytoplasmic adaptor proteins with a common arrangement of domains and conserved regions, including a CDC15 N-terminal domain, which contains a RAEYL motif and a coiled-coil region, and a C-terminal SH3 domain. By searching an EST database for novel members of the PACSIN family, Ritter et al. (1999) identified ESTs encoding human and mouse PACSIN2. The complete human PACSIN2 coding sequence, obtained from 2 overlapping retina ESTs, encodes a deduced 486-amino acid protein that shares 93.6% sequence identity with mouse Pacsin2. The PACSIN2 proteins contain a CDC15 N-terminal domain, a C-terminal SRC (190090) homology-3 (SH3) domain, 3 conserved regions specific to the PACSIN family, and 3 asn-pro-phe (NPF) motifs, which potentially bind to EH domains. The PACSIN2 proteins share high sequence similarity with chicken FAP52 and mouse Pacsin1 (606512). However, compared to these proteins, PACSIN2 proteins have a 41-amino acid insertion, which contains 1 NPF motif. In contrast to the restricted neural expression of mouse Pacsin1 (Plomann et al., 1998), Northern blot analysis detected mouse Pacsin2 expression in all tissues examined, with the highest levels in brain, heart, skeletal muscle, and ovary. Immunofluorescence microscopy of recombinant Pacsin2 expressed in fibroblasts showed a broad, vesicle-like cytoplasmic distribution that appeared to partially overlap with the distributions of both the actin filament and microtubule networks. Unlike FAP52, Pacsin2 was not detected at focal contacts. Ritter et al. (1999) suggested that PACSIN2 may participate in the organization of the actin cytoskeleton and the regulation of vesicular traffic.
By Northern blot analysis, Sumoy et al. (2001) detected ubiquitous distribution of a 3.4-kb PACSIN2 transcript, with marked expression in heart, and a predominant 2.4-kb alternate transcript in pancreas.
Senju et al. (2011) reported that the PACSIN2 protein contains an N-terminal extended FES (190030)-CIP4 (TRIP10; 604504) homology BAR (F-BAR) domain, in addition to the C-terminal SH3 domain and NPF motifs. Immunogold electron microscopy localized endogenous PACSIN2 to the neck region of caveolae in HeLa cells. PACSIN2 also localized to the plasma membrane and cytosol.
De Kreuk et al. (2012) stated that PACSIN2 localized to RAB5 (see 179512)-positive endosomes.
Senju et al. (2011) found that overexpression of the PACSIN2 F-BAR domain in HeLa cells altered the localization of caveolin-1 (CAV1; 601047) and caused mesh-like plasma membrane invaginations. The isolated F-BAR domain of PACSIN2 bound the N terminus of CAV1 more strongly than full-length PACSIN2. Senju et al. (2011) determined that an intramolecular interaction between the SH3 and F-BAR domains of PACSIN2 was autoinhibitory and that CAV1 interrupted this interaction. In addition to binding CAV1, the F-BAR domain of PACSIN2 simultaneously bound the plasma membrane and induced membrane tubulation. Knockdown of PACSIN2 in HeLa cells via small interfering RNA reduced the number of CAV1-positive invaginations, increased the diameter of caveolae necks, increased caveolae depth, and interfered with recruitment of dynamin-2 (DNM2; 602378) for caveolae fission. The presence of PACSIN2 at caveolae necks appeared to correspond to membrane tubulating activity, since PACSIN2-induced tubules were antagonized by dynamin-2. Senju et al. (2011) concluded that PACSIN2 induces membrane tubulation for caveolae sculpting and fission.
De Kreuk et al. (2012) observed that EGF (131530) and EGF receptor (EGFR; 131550) were internalized into PACSIN2-positive endosomes in HeLa cells. Knockdown of PACSIN2 increased the surface level of EGFR and enhanced EGF-stimulated EGFR phosphorylation and downstream signaling via ERK (see 176948) and AKT (see 164730). Knockdown of PACSIN2 did not inhibit EGFR internalization, but blocked its degradation. Expression of PACSIN2 mutants with inactivating mutations in the SH3 domain or BAR domain increased surface expression of EGFR in unstimulated cells. Knockdown of PACSIN2 also elevated signaling initiated by HGF (142409) in HeLa cells and by TNF-alpha (TNF; 191160) and VEGF (VEGFA; 192240) in human endothelial cells. De Kreuk et al. (2012) hypothesized that PACSIN2 may be a general regulator of growth factor receptor surface expression, possibly by regulating receptor sorting.
Sumoy et al. (2001) stated that the PACSIN2 gene maps to 22q13.
de Kreuk, B.-J., Anthony, E. C., Geerts, D., Hordijk, P. L. The F-BAR protein PACSIN2 regulates epidermal growth factor receptor internalization. J. Biol. Chem. 287: 43438-43453, 2012. [PubMed: 23129763] [Full Text: https://doi.org/10.1074/jbc.M112.391078]
Plomann, M., Lange, R., Vopper, G., Cremer, H., Heinlein, U. A. O., Scheff, S., Baldwin, S. A., Leitges, M., Cramer, M., Paulsson, M., Barthels, D. PACSIN, a brain protein that is upregulated upon differentiation into neuronal cells. Europ. J. Biochem. 256: 201-211, 1998. [PubMed: 9746365] [Full Text: https://doi.org/10.1046/j.1432-1327.1998.2560201.x]
Ritter, B., Modregger, J., Paulsson, M., Plomann, M. PACSIN 2, a novel member of the PACSIN family of cytoplasmic adapter proteins. FEBS Lett. 454: 356-362, 1999. [PubMed: 10431838] [Full Text: https://doi.org/10.1016/s0014-5793(99)00830-3]
Senju, Y., Itoh, Y., Takano, K., Hamada, S., Suetsugu, S. Essential role of PACSIN2/syndapin-II in caveolae membrane sculpting. J. Cell Sci. 124: 2032-2040, 2011. [PubMed: 21610094] [Full Text: https://doi.org/10.1242/jcs.086264]
Sumoy, L., Pluvinet, R., Andreu, N., Estivill, X., Escarceller, M. PACSIN 3 is a novel SH3 domain cytoplasmic adapter protein of the pacsin-syndapin-FAP52 gene family. Gene 262: 199-205, 2001. [PubMed: 11179684] [Full Text: https://doi.org/10.1016/s0378-1119(00)00531-x]