Alternative titles; symbols
HGNC Approved Gene Symbol: CYTH1
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:78,674,048-78,782,273 (from NCBI)
One of the major mediators of the inborn or 'natural' immune system is the natural killer (NK) cell. Dixon et al. (1993) prepared a subtractive cDNA library from human NK cells and characterized 13 unique clones. A clone named B2-1 was highly expressed in both NK and T cells, but was very weakly expressed or absent in several other cell lines. The deduced protein was highly homologous to the yeast protein SEC7, which is located in the Golgi apparatus and is thought to be involved in transporting proteins through the Golgi complex. B2-1 was the only known human protein with significant homology to SEC7 and may be one of the human equivalents of the yeast secretory proteins.
Using a yeast 2-hybrid screen of a T-cell leukemia cell line with the intracellular portion of CD18 (ITGB2; 600065) as bait, Kolanus et al. (1996) isolated a cDNA encoding cytohesin-1 (PSCD1) and a partial cDNA encoding PSCD2L (602488), which they designated cts18.1. PSCD1 is 88% identical to the PSCD2L fragment. The predicted 398-amino acid PSCD1 protein contains a central 200-residue SEC7 domain and a C-terminal pleckstrin homology (PH) domain. Western blot analysis showed expression of a 47-kD protein, particularly, but not exclusively, in lymphoid cells.
By EST analysis, Ikenouchi and Umeda (2010) found that CYTH1 was ubiquitously expressed in epithelial tissues. In mouse intestinal epithelial cells, Cyth1 colocalized with Zo1 (TJP1; 601009) at tight junctions. In EpH4 mouse mammary epithelial cells, Cyth1 localized to both primordial adherens junctions and tight junctions.
Kolanus et al. (1996) found that overexpression of a full-length PSCD1 protein or of the SEC7 domain only induced CD18-dependent binding to ICAM1 (147840), whereas the PSCD1 PH domain specifically inhibited adhesion. Binding analysis indicated that the SEC7 domain, but not the PH domain, interacts with the cytoplasmic domain of CD18 but not with other cell surface receptors or protein-tyrosine kinases tested. Kolanus et al. (1996) concluded that PSCD1 specifically regulates the adhesive function of beta-2 integrins in lymphocytes.
The induction of a transformed cellular phenotype by viruses requires the modulation of signaling pathways through viral proteins. Kliche et al. (2001) showed that the phenotypic changes induced by the kaposin A protein of human herpesvirus-8 are mediated through its direct interaction with cytohesin-1, a guanine nucleotide exchange factor (GEF) for ARF GTPases (e.g., ARF1; 103180) and regulator of integrin-mediated cell adhesion. Focus formation, stress fiber dissolution, and activation of the ERK1 (601795)/ERK2 (176948) mitogen-activated protein kinase (MAPK) signal cascade were reverted by a cytohesin-1 glu157-to-lys mutant, which is deficient in catalyzing guanine nucleotide exchange. Furthermore, liposome-embedded kaposin A was found to specifically stimulate cytohesin-1-dependent GTP binding of myristoylated ARF1 in vitro.
Hafner et al. (2006) used an aptamer displacement screen to identify SecinH3, a small Sec7 domain-specific molecular antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization, integrin activation, or integrin signaling. The application of SecinH3 in human liver cells showed that insulin receptor complex-associated cytohesins are required for insulin signaling. SecinH3-treated mice showed increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid, and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, Hafner et al. (2006) concluded that cytohesin inhibition results in hepatic insulin resistance.
Vitale et al. (2000) found that cytohesin-1 interacted with ARF domain protein-1 (ARD1, or TRIM23; 601747) in a yeast 2-hybrid screen of a human liver cDNA library. ARD1-GDP interacted well with cytohesin-1 but poorly with cytohesin-2 (PSCD2; 602488), and cytohesin-1 accelerated binding of a nonhydrolyzable GTP analog to ARD1. Mutation analysis showed that the effector region of the ARF domain of ARD1 interacted with the Sec7 domain of cytohesin-1. Physical association between these domains was highly dependent on experimental conditions, and a free Mg(2+) concentration that favored nucleotide release from ARD1 and accumulation of the nucleotide-free ARD1 form also favored interaction between ARD1 and cytohesin-1. In transfected COS-7 cells, cytohesin-1 was distributed throughout the cell and was also present in the nucleus. ARD1 associated with vesicular structures concentrated around the nucleus and scattered throughout the cytoplasm, corresponding to Golgi and lysosomes, respectively. A constitutively GDP-bound form of ARD1 showed a similar distribution, whereas a constitutively GTP-bound form of ARD1 was concentrated close to the nucleus in a Golgi-like distribution only. When ARD1 or its GDP- and GTP-bound forms were coexpressed with cytohesin-1, only the GDP-bound form showed any change in distribution or colocalization with cytohesin-1. In 90% of cells coexpressing the proteins, the GDP-bound form of ARD1 was distributed throughout the cell, except for the nucleus, and largely colocalized with cytohesin-1. In less than 10% of cells coexpressing the proteins, the GDP-bound form of ARD1 and cytohesin-1 colocalized in lysosomes.
Ikenouchi and Umeda (2010) found that pharmacologic inhibition of cytohesin in EpH4 cells blocked activation of Arf6 (600464), delaying calcium-dependent maturation of primordial adherens junctions into belt-like adherens junctions and development of transepithelial electrical resistance. Overexpression of dominant-negative forms of Cyth1 or Grp1 (CYTH3; 605081) also blocked calcium-dependent formation of belt-like adherens junctions. Yeast 2-hybrid analysis revealed that Cyth1 interacted with Frmd4a (616305). Frmd4a also interacted with Par3 (PARD3; 606745), which functions in a complex required for maturation of adherens junctions. Cyth1, Frmd4a, and Par3 colocalized at primordial adherens junctions and tight junctions in EpH4 cells. Knockdown of Frmd4a alone had little effect on the development of polarity in EpH4 cells, but double knockdown of Frmd4a and Grsp1 (FRMD4B) impaired localization of Cyth1 at primordial adherens junctions and inhibited formation of belt-like adherens junctions and tight junctions. Exogenous expression of human FRMD4A or GRSP1 rescued the phenotype of Frmd4a and Grsp1 double-knockdown cells. Ikenouchi and Umeda (2010) concluded that a PAR3-FRMD4A-CYTH1 complex ensures accurate activation of ARF6 at adherens junctions during polarization of epithelial cells.
By genomic sequence analysis, Ogasawara et al. (2000) determined that the PSCD1 gene contains at least 14 exons, including a 3-bp exon 10 also present in PSCD2 and PSCD3 (605081) but not in PSCD4 (606514) that results in the insertion of a single glycine into the variable loop between the first and second beta sheets in the pleckstrin homology domain.
Dixon et al. (1993) showed by PCR analysis of a human/rodent hybrid panel that the B2-1 gene is located on chromosome 17. Fluorescence in situ hybridization localized the gene to 17q25.
Dixon, B., Mansour, M., Pohajdak, B. Assignment of human B2-1 gene (D17S811E) to chromosome 17qter by PCR analysis of somatic cell hybrids and fluorescence in situ hybridization. Cytogenet. Cell Genet. 63: 42-44, 1993. [PubMed: 8449036] [Full Text: https://doi.org/10.1159/000133498]
Hafner, M., Schmitz, A., Grune, I., Srivatsan, S. G., Paul, B., Kolanus, W., Quast, T., Kremmer, E., Bauer, I., Famulok, M. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444: 941-944, 2006. [PubMed: 17167487] [Full Text: https://doi.org/10.1038/nature05415]
Ikenouchi, J., Umeda, M. FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex. Proc. Nat. Acad. Sci. 107: 748-753, 2010. [PubMed: 20080746] [Full Text: https://doi.org/10.1073/pnas.0908423107]
Kliche, S., Nagel, W., Kremmer, E., Atzler, C., Ege, A., Knorr, T., Koszinowski, U., Kolanus, W., Haas, J. Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1. Molec. Cell 7: 833-843, 2001. [PubMed: 11336706] [Full Text: https://doi.org/10.1016/s1097-2765(01)00227-1]
Kolanus, W., Nagel, W., Schiller, B., Zeitlmann, L., Godar, S., Stockinger, H., Seed, B. Alpha-L-beta-2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 86: 233-242, 1996. [PubMed: 8706128] [Full Text: https://doi.org/10.1016/s0092-8674(00)80095-1]
Ogasawara, M., Kim, S.-C., Adamik, R., Togawa, A., Ferrans, V. J., Takeda, K., Kirby, M., Moss, J., Vaughan, M. Similarities in function and gene structure of cytohesin-4 and cytohesin-1, guanine nucleotide-exchange proteins for ADP-ribosylation factors. J. Biol. Chem. 275: 3221-3230, 2000. [PubMed: 10652308] [Full Text: https://doi.org/10.1074/jbc.275.5.3221]
Vitale, N., Pacheco-Rodriguez, G., Ferrans, V. J., Riemenschneider, W., Moss, J., Vaughan, M. Specific functional interaction of human cytohesin-1 and ADP-ribosylation factor domain protein (ARD1). J. Biol. Chem. 275: 21331-21339, 2000. [PubMed: 10748148] [Full Text: https://doi.org/10.1074/jbc.M909642199]