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Gene Review

SIPA1  -  signal-induced proliferation-associated 1

Homo sapiens

Synonyms: GTPase-activating protein Spa-1, SPA1, Signal-induced proliferation-associated protein 1, Sipa-1, p130 SPA-1
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Disease relevance of SIPA1


Psychiatry related information on SIPA1


High impact information on SIPA1


Chemical compound and disease context of SIPA1


Biological context of SIPA1

  • Fluorescence in situ hybridization (FISH) analysis using the human genomic clones indicated that SIPA1 was indeed mapped to chromosome 11q13, most likely to the 11q13.3 subregion [9].
  • Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression [7].
  • When SPA-1 was conditionally induced after the established cell adhesion, the cells gradually rounded up and detached from the dish [10].
  • SIPA-1 consists of 16 exons with highly conserved exon-intron boundaries [11].
  • Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR [1].

Anatomical context of SIPA1

  • SPA-1 transiently expressed in HeLa cells was mostly localized at the cortical cytoskeleton and induced rounding up of the cells, whereas C3G-F conversely induced extensive cell spreading [10].
  • Retroviral overexpression of SPA-1 in promyelocytic 32D cells also inhibited both activation of Rap1 and induction of cell adhesion by granulocyte colony stimulating factor without affecting differentiation [10].
  • Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice [2].
  • Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo [2].
  • In the present study, we showed that the MPDs in SPA-1(-/-) mice were associated with the increased hematopoietic stem cells expressing LFA-1 in bone marrow and their premature mobilization to spleen with extensive extramedullary hematopoiesis, resembling human chronic myelogenous leukemia (CML) [12].

Associations of SIPA1 with chemical compounds

  • AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1 [13].
  • The effects of low concentrations of epinephrine, ADP, and collagen on SIPA under both low shear (12 dyne/cm2) and high shear (108 dyne/cm2) force were investigated [6].
  • To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPA-dependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of alphaIIbbeta3 blockers [14].
  • In contrast, neither RGDS peptide nor MoAb 7E3, both known to block alphaIIbbeta3 engagement, had any effect on SIPA and pp125FAK [14].
  • SIPA-induced MLC phosphorylation occurred exclusively through released nucleotides and selective antagonism of P2X(1) with MRS2159-reduced SIPA, ATP release, and potently inhibited MLC phosphorylation [15].

Physical interactions of SIPA1

  • In vitro binding studies using truncated fragments and their mutants suggested that SPA-1 was bound to the PDZ domain of AF-6 via probable internal PDZ ligand motif within the GAP-related domain [13].

Co-localisations of SIPA1

  • Immunostaining analysis revealed that SPA-1 and RapV12 were co-localized with AF-6 at the cell attachment sites [13].

Regulatory relationships of SIPA1

  • Recent studies reveal that deregulated Rap1 activation in SPA-1-deficient mice causes enhanced expansion of the bone marrow hematopoietic progenitors, but induces progressive unresponsiveness or anergy in T cells [3].

Other interactions of SIPA1

  • Human genomic clones, which hybridized with both mouse and human SIPA1 cDNA but not with RAP1GAP cDNA, were then isolated [9].
  • These results suggested that products of SPA-1 and rap1GAP genes, albeit comparable GAP activity for Rap1 and Rap2, functioned in the distinct contexts depending on cell types and/or states [16].
  • During the course of cloning SIPA-1, the MEN1 gene was identified, thus excluding human SIPA-1 as a candidate for this disease [11].
  • SPA-1 cDNA encodes a 130-kDa protein (p130(SPA-1)) consisting of proline-rich regions and rap1GAP-related domain followed by a coiled-coil stretch [16].
  • The predicted SIPA-1 protein is highly homologous to the mouse protein, particularly in the region of the GAP-related domain at the amino terminus and the leucine zipper at the carboxy terminus [11].

Analytical, diagnostic and therapeutic context of SIPA1

  • This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA [5].
  • SIPA was quantitated by flow cytometry as the disappearance of single platelets (DSP) in the sheared sample in the presence of vWF, relative to a control in the absence of shear and vWF [17].
  • OBJECTIVES: The goal of this study was to identify differences in shear-induced platelet aggregation (SIPA) between patients who did or did not experience subacute stent thrombosis (SAT) [18].
  • The antibody inhibited completely ristocetin-induced platelet aggregation (RIPA) and high shear stress-induced platelet aggregation (SIPA) [19].
  • RESULTS: There were significant increases in not only adenosine phosphate (ADP)- and collagen-induced platelet aggregation but also in SIPA during exercise by the patient control group [20].


  1. Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Crawford, N.P., Ziogas, A., Peel, D.J., Hess, J., Anton-Culver, H., Hunter, K.W. Breast Cancer Res. (2006) [Pubmed]
  2. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Ishida, D., Kometani, K., Yang, H., Kakugawa, K., Masuda, K., Iwai, K., Suzuki, M., Itohara, S., Nakahata, T., Hiai, H., Kawamoto, H., Hattori, M., Minato, N. Cancer Cell (2003) [Pubmed]
  3. Rap1 and SPA-1 in hematologic malignancy. Kometani, K., Ishida, D., Hattori, M., Minato, N. Trends in molecular medicine. (2004) [Pubmed]
  4. Measurement error in alcohol consumption: the Swiss Health Survey. Rehm, J., Spuhler, T. European journal of clinical nutrition. (1993) [Pubmed]
  5. Shear-induced platelet aggregation is inhibited by in vivo infusion of an anti-glycoprotein IIb/IIIa antibody fragment, c7E3 Fab, in patients undergoing coronary angioplasty. Konstantopoulos, K., Kamat, S.G., Schafer, A.I., Bañez, E.I., Jordan, R., Kleiman, N.S., Hellums, J.D. Circulation (1995) [Pubmed]
  6. Epinephrine augments von Willebrand factor-dependent shear-induced platelet aggregation. Goto, S., Ikeda, Y., Murata, M., Handa, M., Takahashi, E., Yoshioka, A., Fujimura, Y., Fukuyama, M., Handa, S., Ogawa, S. Circulation (1992) [Pubmed]
  7. Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization. Farina, A., Hattori, M., Qin, J., Nakatani, Y., Minato, N., Ozato, K. Mol. Cell. Biol. (2004) [Pubmed]
  8. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Minami, N., Suzuki, Y., Yamamoto, M., Kihira, H., Imai, E., Wada, H., Kimura, Y., Ikeda, Y., Shiku, H., Nishikawa, M. Life Sci. (1997) [Pubmed]
  9. Mitogen-inducible SIPA1 is mapped to the conserved syntenic groups of chromosome 19 in mouse and chromosome 11q13.3 centromeric to BCL1 in human. Wada, Y., Kubota, H., Maeda, M., Taniwaki, M., Hattori, M., Imamura, S., Iwai, K., Minato, N. Genomics (1997) [Pubmed]
  10. Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. Tsukamoto, N., Hattori, M., Yang, H., Bos, J.L., Minato, N. J. Biol. Chem. (1999) [Pubmed]
  11. Genomic organization and cloning of the human homologue of murine Sipa-1. Ebrahimi, S., Wang, E., Udar, N., Arnold, E., Burbee, D., Small, K., Sawicki, M.P. Gene (1998) [Pubmed]
  12. Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL-Expressing Hematopoietic Progenitors in a Mouse Model. Kometani, K., Aoki, M., Kawamata, S., Shinozuka, Y., Era, T., Taniwaki, M., Hattori, M., Minato, N. Cancer Res. (2006) [Pubmed]
  13. AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1. Su, L., Hattori, M., Moriyama, M., Murata, N., Harazaki, M., Kaibuchi, K., Minato, N. J. Biol. Chem. (2003) [Pubmed]
  14. Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of alpha IIb beta 3 engagement. Mekrache, M., Bachelot-Loza, C., Ajzenberg, N., Saci, A., Legendre, P., Baruch, D. Blood (2003) [Pubmed]
  15. ATP augments von Willebrand factor-dependent shear-induced platelet aggregation through Ca2+-calmodulin and myosin light chain kinase activation. Oury, C., Sticker, E., Cornelissen, H., De Vos, R., Vermylen, J., Hoylaerts, M.F. J. Biol. Chem. (2004) [Pubmed]
  16. Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product. Kurachi, H., Wada, Y., Tsukamoto, N., Maeda, M., Kubota, H., Hattori, M., Iwai, K., Minato, N. J. Biol. Chem. (1997) [Pubmed]
  17. Platelet aggregation induced by a monoclonal antibody to the A1 domain of von Willebrand factor. Depraetere, H., Ajzenberg, N., Girma, J.P., Lacombe, C., Meyer, D., Deckmyn, H., Baruch, D. Blood (1998) [Pubmed]
  18. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study. Ajzenberg, N., Aubry, P., Huisse, M.G., Cachier, A., El Amara, W., Feldman, L.J., Himbert, D., Baruch, D., Guillin, M.C., Steg, P.G. J. Am. Coll. Cardiol. (2005) [Pubmed]
  19. Identification of the binding site for an alloantibody to von Willebrand factor which inhibits binding to glycoprotein Ib within the amino-terminal region flanking the A1 domain. Shibata, M., Shima, M., Fujimura, Y., Takahashi, Y., Nakai, H., Sakurai, Y., Asatani, M., Nomura, A., Take, H., Giddings, J.C., Yoshioka, A. Thromb. Haemost. (1999) [Pubmed]
  20. Inhibition by combined therapy with ticlopidine and aspirin of enhanced platelet aggregation during physical exercise in patients with coronary artery disease. Kitai, T., Nishikawa, M., Tanigawa, T., Okinaka, T., Wada, H., Shiku, H., Ikeda, Y., Ito, M., Isaka, N., Nakano, T. Am. Heart J. (2001) [Pubmed]
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