* 613324

SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13


Alternative titles; symbols

APC-STIMULATED GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; ASEF2


HGNC Approved Gene Symbol: SPATA13

Cytogenetic location: 13q12.12     Genomic coordinates (GRCh38): 13:23,979,802-24,307,069 (from NCBI)


TEXT

Cloning and Expression

Hamann et al. (2007) identified 3 splice variants of SPATA13, which they called ASEF2. The variants differ at their 5-prime ends, and all 3 encode proteins containing a putative APC (611731)-binding region (ABR), an SRC (190090) homology-3 (SH3) domain, a DBL (MCF2; 311030) homology (DH) domain, a pleckstrin (PLEK; 173570) homology (PH) domain, and a C-terminal tail. A deduced 652-amino acid ASEF2 protein shares 54% identity with ASEF1 (ARHGEF4; 605216) and 48% identity with collybistin (ARHGEF9; 300429). Northern blot analysis detected variable expression of at least 2 ASEF2 transcripts in all tissues examined.

By database analysis, Kawasaki et al. (2007) identified 4 SPATA13 splice variants, ASEF2A, ASEF2B, ASEF2C, and ASEF2D, which encode ASEF2 isoforms of 574, 652, 1,167, and 1,339 amino acids, respectively. All 4 isoforms have the ABR, SH3, DH, and PH domains and differ only in their N- and C-terminal sequences. Northern blot analysis detected ASEF2 transcripts of 8.7 and 6.2 kb. Expression was high in placenta, spleen, and kidney, moderate in lung, small intestine, liver, brain, and heart, and low in skeletal muscle. RT-PCR analysis detected expression of ASEF2A and ASEF2D, but not ASEF2B and ASEF2C, in colorectal epithelium.

Using qPCR, Waseem et al. (2020) analyzed expression of 2 SPATA13 transcripts, which they designated SP-652 and SP-1277 based on their amino acid length. The transcripts were detected in all 17 cell lines tested, including eye, liver, kidney, cervix, esophagus, fibrosarcoma, breast, skin, head and neck cancers, and oral dysplasias. The authors also used qPCR to investigate mRNA expression of SP-1277 and SP-652 in human iris, ciliary epithelium, retinal pigmented epithelium (RPE), retina, cornea, and lens. The SP-652 transcript showed highest expression in cornea and lens, whereas the SP-1277 transcript was highest in cornea and ciliary epithelium, suggesting that SP-1277 is the predominant transcript in tissues most affected in primary angle-closure glaucoma (see MOLECULAR GENETICS). Using antibodies specific for SP-1277 to analyze mouse and human eye sections, the authors observed reactivity with both pigmented and nonpigmented ciliary epithelia, iris sphincter and dilator muscles, corneal epithelium, and retinal outer nuclear, inner nuclear, and ganglion cell layers.


Gene Structure

Hamann et al. (2007) determined that the SPATA13 gene contains at least 14 exons.


Mapping

Hartz (2010) mapped the SPATA13 gene to chromosome 13q12.12 based on an alignment of the SPATA13 sequence (GenBank AK055770) with the genomic sequence (GRCh37).


Gene Function

Hamann et al. (2007) found that both ASEF1 and ASEF2 were guanine nucleotide exchange factors (GEFs) for CDC42 (116952), but not for RAC1 (602048) or RHOA (165390). ASEF2 required the lipid-modified form of CDC42. Using deletion mutants, Hamann et al. (2007) showed that the tandem N-terminal ABR and SH3 domain (ABRSH3) of the ASEF proteins was required to bind the armadillo repeat region of APC. ABRSH3 also functioned in an autoinhibitory reaction by binding the C-terminal tails of ASEF1 and ASEF2 and inhibiting their GEF activities. Deletion of ABRSH3 or coexpression of the APC armadillo repeat sequence with full-length ASEF2 stimulated filopodia formation in transfected HeLa cells. Hamann et al. (2007) concluded that activation of ASEF1 and ASEF2 involves binding of APC to ABRSH3, which disrupts the autoinhibitory interaction of ABRSH3 with the ASEF C-terminal tail and allows GDP/GTP exchange on CDC42.

Kawasaki et al. (2007) showed that ASEF2 functioned as a GEF for both CDC42 and RAC1 in HEK293 and HeLa cells, and that APC increased its GEF activity. Overexpression of ASEF2 in Madin-Darby canine kidney (MDCK) cells induced membrane ruffling and Rac1-mediated lamellipodia formation, while overexpression of ASEF2 in HeLa cells induced membrane ruffling and CDC42-mediated filopodia formation. ASEF2 also increased cell motility of MDCK cells. Conversely, knockdown of ASEF2 in SW480 human colon cancer cells via short interfering RNA decreased cell motility. Immunoprecipitation analysis confirmed direct interaction between ASEF2 and APC, and mutation analysis revealed that both the ABR and SH3 domains of ASEF2 were required for the interaction. Kawasaki et al. (2007) concluded that ASEF2 activates RAC1 and CDC42 and that its activity is regulated by APC.

Using immunoprecipitation, mass spectrometric, and Western blot analyses, Sagara et al. (2009) found that ASEF2 interacted with neurabin II (PPP1R9B; 603325) in human embryonic kidney cells. In response to HGF (142409) treatment of HeLa cells, ASEF2, neurabin II, and APC accumulated and colocalized in lamellipodia and membrane ruffles. RNA interference experiments showed that ASEF2, neurabin II, and APC were involved in HGF-induced cell migration. Furthermore, knockdown of neurabin II resulted in suppression of ASEF2-induced filopodia formation.


Molecular Genetics

For discussion of a possible association between variation in the SPATA13 gene and primary angle-closure glaucoma, see GLCC (618880).


Animal Model

Bourbia et al. (2019) found that Spata13 knockout in mice had no effect on viability, memory, anxiety, nociception, or spine counts. However, both male and female Spata13 -/- mice showed increased levels of subordinate behavior compared with wildtype. Moreover, Spata13 -/- females displayed increased activity in the dark phase of the light dark cycle, indicating increased nocturnal activity, compared with wildtype.


REFERENCES

  1. Bourbia, N., Chandler, P., Codner, G., Banks, G., Nolan, P. M. The guanine nucleotide exchange factor, Spata13, influences social behaviour and nocturnal activity. Mammalian Genome 30: 54-62, 2019. [PubMed: 31020388, images, related citations] [Full Text]

  2. Hamann, M. J., Lubking, C. M., Luchini, D. N., Billadeau, D. D. Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element. Molec. Cell. Biol. 27: 1380-1393, 2007. [PubMed: 17145773, images, related citations] [Full Text]

  3. Hartz, P. A. Personal Communication. Baltimore, Md. 3/19/2010.

  4. Kawasaki, Y., Sagara, M., Shibata, Y., Shirouzu, M., Yokoyama, S., Akiyama, T. Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42. Oncogene 26: 7620-7627, 2007. [PubMed: 17599059, related citations] [Full Text]

  5. Sagara, M., Kawasaki, Y., Iemura, S., Natsume, T., Takai, Y., Akiyama, T. Asef2 and Neurabin2 cooperatively regulate actin cytoskeletal organization and are involved in HGF-induced cell migration. Oncogene 28: 1357-1365, 2009. [PubMed: 19151759, related citations] [Full Text]

  6. Waseem, N. H., Low, S., Shah, A. Z., Avisetti, D., Ostergaard, P., Simpson, M., Niemiec, K. A., Martin-Martin, B., Aldehlawi, H., Usman, S., Lee, P. S., Khawaja, A. P., and 15 others. Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma. PLoS Genet. 16: e1008721, 2020. [PubMed: 32339198, images, related citations] [Full Text]


Bao Lige - updated : 09/01/2023
Marla J. F. O'Neill - updated : 06/29/2021
Patricia A. Hartz - updated : 1/6/2011
Creation Date:
Patricia A. Hartz : 3/24/2010
mgross : 09/01/2023
alopez : 06/29/2021
mgross : 01/24/2011
terry : 1/6/2011
mgross : 3/24/2010

* 613324

SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13


Alternative titles; symbols

APC-STIMULATED GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; ASEF2


HGNC Approved Gene Symbol: SPATA13

Cytogenetic location: 13q12.12     Genomic coordinates (GRCh38): 13:23,979,802-24,307,069 (from NCBI)


TEXT

Cloning and Expression

Hamann et al. (2007) identified 3 splice variants of SPATA13, which they called ASEF2. The variants differ at their 5-prime ends, and all 3 encode proteins containing a putative APC (611731)-binding region (ABR), an SRC (190090) homology-3 (SH3) domain, a DBL (MCF2; 311030) homology (DH) domain, a pleckstrin (PLEK; 173570) homology (PH) domain, and a C-terminal tail. A deduced 652-amino acid ASEF2 protein shares 54% identity with ASEF1 (ARHGEF4; 605216) and 48% identity with collybistin (ARHGEF9; 300429). Northern blot analysis detected variable expression of at least 2 ASEF2 transcripts in all tissues examined.

By database analysis, Kawasaki et al. (2007) identified 4 SPATA13 splice variants, ASEF2A, ASEF2B, ASEF2C, and ASEF2D, which encode ASEF2 isoforms of 574, 652, 1,167, and 1,339 amino acids, respectively. All 4 isoforms have the ABR, SH3, DH, and PH domains and differ only in their N- and C-terminal sequences. Northern blot analysis detected ASEF2 transcripts of 8.7 and 6.2 kb. Expression was high in placenta, spleen, and kidney, moderate in lung, small intestine, liver, brain, and heart, and low in skeletal muscle. RT-PCR analysis detected expression of ASEF2A and ASEF2D, but not ASEF2B and ASEF2C, in colorectal epithelium.

Using qPCR, Waseem et al. (2020) analyzed expression of 2 SPATA13 transcripts, which they designated SP-652 and SP-1277 based on their amino acid length. The transcripts were detected in all 17 cell lines tested, including eye, liver, kidney, cervix, esophagus, fibrosarcoma, breast, skin, head and neck cancers, and oral dysplasias. The authors also used qPCR to investigate mRNA expression of SP-1277 and SP-652 in human iris, ciliary epithelium, retinal pigmented epithelium (RPE), retina, cornea, and lens. The SP-652 transcript showed highest expression in cornea and lens, whereas the SP-1277 transcript was highest in cornea and ciliary epithelium, suggesting that SP-1277 is the predominant transcript in tissues most affected in primary angle-closure glaucoma (see MOLECULAR GENETICS). Using antibodies specific for SP-1277 to analyze mouse and human eye sections, the authors observed reactivity with both pigmented and nonpigmented ciliary epithelia, iris sphincter and dilator muscles, corneal epithelium, and retinal outer nuclear, inner nuclear, and ganglion cell layers.


Gene Structure

Hamann et al. (2007) determined that the SPATA13 gene contains at least 14 exons.


Mapping

Hartz (2010) mapped the SPATA13 gene to chromosome 13q12.12 based on an alignment of the SPATA13 sequence (GenBank AK055770) with the genomic sequence (GRCh37).


Gene Function

Hamann et al. (2007) found that both ASEF1 and ASEF2 were guanine nucleotide exchange factors (GEFs) for CDC42 (116952), but not for RAC1 (602048) or RHOA (165390). ASEF2 required the lipid-modified form of CDC42. Using deletion mutants, Hamann et al. (2007) showed that the tandem N-terminal ABR and SH3 domain (ABRSH3) of the ASEF proteins was required to bind the armadillo repeat region of APC. ABRSH3 also functioned in an autoinhibitory reaction by binding the C-terminal tails of ASEF1 and ASEF2 and inhibiting their GEF activities. Deletion of ABRSH3 or coexpression of the APC armadillo repeat sequence with full-length ASEF2 stimulated filopodia formation in transfected HeLa cells. Hamann et al. (2007) concluded that activation of ASEF1 and ASEF2 involves binding of APC to ABRSH3, which disrupts the autoinhibitory interaction of ABRSH3 with the ASEF C-terminal tail and allows GDP/GTP exchange on CDC42.

Kawasaki et al. (2007) showed that ASEF2 functioned as a GEF for both CDC42 and RAC1 in HEK293 and HeLa cells, and that APC increased its GEF activity. Overexpression of ASEF2 in Madin-Darby canine kidney (MDCK) cells induced membrane ruffling and Rac1-mediated lamellipodia formation, while overexpression of ASEF2 in HeLa cells induced membrane ruffling and CDC42-mediated filopodia formation. ASEF2 also increased cell motility of MDCK cells. Conversely, knockdown of ASEF2 in SW480 human colon cancer cells via short interfering RNA decreased cell motility. Immunoprecipitation analysis confirmed direct interaction between ASEF2 and APC, and mutation analysis revealed that both the ABR and SH3 domains of ASEF2 were required for the interaction. Kawasaki et al. (2007) concluded that ASEF2 activates RAC1 and CDC42 and that its activity is regulated by APC.

Using immunoprecipitation, mass spectrometric, and Western blot analyses, Sagara et al. (2009) found that ASEF2 interacted with neurabin II (PPP1R9B; 603325) in human embryonic kidney cells. In response to HGF (142409) treatment of HeLa cells, ASEF2, neurabin II, and APC accumulated and colocalized in lamellipodia and membrane ruffles. RNA interference experiments showed that ASEF2, neurabin II, and APC were involved in HGF-induced cell migration. Furthermore, knockdown of neurabin II resulted in suppression of ASEF2-induced filopodia formation.


Molecular Genetics

For discussion of a possible association between variation in the SPATA13 gene and primary angle-closure glaucoma, see GLCC (618880).


Animal Model

Bourbia et al. (2019) found that Spata13 knockout in mice had no effect on viability, memory, anxiety, nociception, or spine counts. However, both male and female Spata13 -/- mice showed increased levels of subordinate behavior compared with wildtype. Moreover, Spata13 -/- females displayed increased activity in the dark phase of the light dark cycle, indicating increased nocturnal activity, compared with wildtype.


REFERENCES

  1. Bourbia, N., Chandler, P., Codner, G., Banks, G., Nolan, P. M. The guanine nucleotide exchange factor, Spata13, influences social behaviour and nocturnal activity. Mammalian Genome 30: 54-62, 2019. [PubMed: 31020388] [Full Text: https://doi.org/10.1007/s00335-019-09800-9]

  2. Hamann, M. J., Lubking, C. M., Luchini, D. N., Billadeau, D. D. Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element. Molec. Cell. Biol. 27: 1380-1393, 2007. [PubMed: 17145773] [Full Text: https://doi.org/10.1128/MCB.01608-06]

  3. Hartz, P. A. Personal Communication. Baltimore, Md. 3/19/2010.

  4. Kawasaki, Y., Sagara, M., Shibata, Y., Shirouzu, M., Yokoyama, S., Akiyama, T. Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42. Oncogene 26: 7620-7627, 2007. [PubMed: 17599059] [Full Text: https://doi.org/10.1038/sj.onc.1210574]

  5. Sagara, M., Kawasaki, Y., Iemura, S., Natsume, T., Takai, Y., Akiyama, T. Asef2 and Neurabin2 cooperatively regulate actin cytoskeletal organization and are involved in HGF-induced cell migration. Oncogene 28: 1357-1365, 2009. [PubMed: 19151759] [Full Text: https://doi.org/10.1038/onc.2008.478]

  6. Waseem, N. H., Low, S., Shah, A. Z., Avisetti, D., Ostergaard, P., Simpson, M., Niemiec, K. A., Martin-Martin, B., Aldehlawi, H., Usman, S., Lee, P. S., Khawaja, A. P., and 15 others. Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma. PLoS Genet. 16: e1008721, 2020. [PubMed: 32339198] [Full Text: https://doi.org/10.1371/journal.pgen.1008721]


Contributors:
Bao Lige - updated : 09/01/2023
Marla J. F. O'Neill - updated : 06/29/2021
Patricia A. Hartz - updated : 1/6/2011

Creation Date:
Patricia A. Hartz : 3/24/2010

Edit History:
mgross : 09/01/2023
alopez : 06/29/2021
mgross : 01/24/2011
terry : 1/6/2011
mgross : 3/24/2010