| Written | 2010-05 | Masakazu Hattori |
| Laboratory of Host Defense, Department of Bioscience, Graduate School of Science, Kitasato University, Sagamihara, Kanagawa, 228-8555, Japan |
| Identity |
| Alias_symbol (synonym) | SPA1 |
| Other alias | MGC102688 |
| MGC17037 | |
| HGNC (Hugo) | SIPA1 |
| LocusID (NCBI) | 6494 |
| Atlas_Id | 46282 |
| Location | 11q13.1 [Link to chromosome band 11q13] |
| Location_base_pair | Starts at 65640121 and ends at 65650920 bp from pter ( according to hg19-Feb_2009) [Mapping SIPA1.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| DNA/RNA |
| Note | History and nomenclature: SIPA1 gene, originally referred to as SPA-1, was first isolated in 1995 as the secondary response gene transcriptionally induced in the lymphoid cells by the stimulation with mitogenic cytokines or cross-linking antigen receptors. |
 | |
| Structure of the SIPA1 gene. | |
| Description | The SIPA1 gene spans 12.8 kb of the genome and is characterized by 16 exons; exon 1, 91 bp of exon 2 and the 3' 205 bp of exon 16 are untranslated. The figure shows the general structure of the gene. |
| Transcription | A 3.6 kb transcript is detected preferentially in lymphohematopoietic tissues and certain cancer cells. Two alternatively spliced variants encoding the same isoform have been characterized to date. |
| Protein |
| Description | The SIPA1 protein, SPA-1, contains 1042 amino-acids (130 KDa); contains Rap GTPase-activating (GAP) domain (350-539), PDZ domain (685-759) and leucine zipper like domain (964-1042) which resembles myosin tail. |
| Expression | SPA-1 is most abundantly expressed in lymphohematopoietic tissues including bone marrow, thymus and spleen. |
| Localisation | Localized in various intracellular compartments, such as actin cytoskeleton, plasma membranes, and possibly nuclei, depending on the cell type and specific protein interaction via the PDZ domain. |
| Function | SPA-1 exhibits a specific GAP activity for Ras-related regulatory proteins Rap1 and Rap2, but not for Ran or other small GTPases. SPA-1 overexpression (abrogating the endogenous Rap1 activation) induced rounding and eventual detachment of inherently adherent cells from extracellular matrix, indicating that Rap1 signals are involved in the regulation of cell adhesion and SPA-1 functions as a negative regulator of cell adhesion. |
| Homology | SPA-1 is highly homologous to human rap1GAPs (RapGA1, RapGA2) at a catalytic domain called the GAP-related domain (GRD) (43% identical amino acids). So far, three homologous molecules of SPA-1 except human rap1GAPs have been reported; SPA-1-like (SPA-L1) (also called E6TP1 or SPAR), SPA-L2, and SPA-L3, all of which share a PDZ domain in addition to a GRD. |
| Mutations |
| Note | SPA-1-deficient (Spa-1-/-) mice also develop age-dependent progression of T-cell unresponsiveness, preceding the overt development of leukemia described as follows. Such Spa-1-/- T cells show defective Ras-mediated ERK activation in response to TCR-stimulation. Stimulation of the Spa-1-/- T cells by TCRs results in the persistence of a high level of Rap1 activation. Spa-1-/- mice exhibit increased basal Rap1GTP selectively in the progenitor population of bone marrow cells, and this is associated with a progressive increase in the hematopoietic stem-cell population as the mice aged. After a long latent period, virtually all of the Spa-1-/- mice develop overt leukemia, which can be classified into several distinct types. A proportion of them show a marked increase in the number of blood leukocytes with only a few blast cells, extensive enlargement of the liver and spleen, and hypercellular bone marrow. The increased leukocytes are predominantly mature granulocytes, or small lymphoid cells bearing an IgM+ CD5+ CD11b+ phenotype with monoclonal immunoglobulin gene-rearrangement patterns, closely resembling human chronic myelogenous leukemia (CML) in the chronic phase, or chronic lymphocytic leukemia (CLL), respectively. Both types of disease can be successfully transferred into severe combined immunodeficient (SCID) mice, indicating that the abnormal proliferation is myeloid progenitor cell autonomous. A minor portion of Spa-1-/- mice show decreased leukocyte numbers with dysplastic myeloid cells accompanied by severe anemia, being reminiscent of the human myelodysplatic syndrome (MDS). Finally, the majority of Spa-1-/- mice develop aggressive lethal leukemia with abundant blast cells of either myeloid or erythroid lineage, which extensively infiltrate into all the vital organs, probably representing the blast crisis of CML in the chronic phase. Blast crisis represents a blastic transformation of leukemia cells that invariably occurs in the course of human CML, and is associated with signs and symptoms of acute leukemia, often with extramedullary disease. In addition to CML-like leukemia, around 15% of over 100 Spa-1-/- mice developed B-lineage cell leukemia. The majority of B220+ leukemic cells exhibited CD5 and Mac1 expression, apparently corresponding to B1 cells. Indeed, the majority of Spa-1-/- mice show a progressive increase in their B1 cell populations in the peritoneal cavity as they aged; this was associated with the generation of anti-dsDNA antibody and lupus-like glomeluronephritis. Many of the Spa-1-/- mice with B1 cell-type leukemia also show a hemolytic autoantibody; this feature highly resembled human B cell chronic lymphocytic leukemia (CLL). Sipa1 is a candidate gene for the Mtes-1 locus which is involved in controlling lung metastasis of mammary tumors in mouse model. In mice, there is a nonsynonymous polymorphism in the Sipa1, either alanine (A) or threonine (T) at the amino acid position 741 in the PDZ domain; all the strains with a Sipa1/741A allele showed high metastatic tendency, whereas those with a Sipa1/741T allele reveal less lung metastasis. Sipa1/741A shows higher Rap1GAP activity than Sipa1/741T in cancer cells, probably due to the altered binding affinity of the PDZ domain for the interacting proteins. In agreement, overexpression of wild type Sipa1 in mammary tumor cells markedly enhanced the lung metastatic activity, whereas knockdown of the endogenous Sipa1 reduces the activity. No pathological mutations have been detected in any leukemia cases. |
| Implicated in |
| Note | |
| Entity | Breast cancer |
| Note | Several studies have shown that germline polymorphisms in SIPA1 are associated with metastasis of breast cancer (Crawford et al., 2006; Hsieh et al., 2009). Crawford et al. examined three SNPs within SIPA1 (one within the promoter (-313G>A: rs931127) and two exonic (545C>T: rs3741378 and 2760G>A: rs746429)). The population (n=300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients using SNP-specfic PCR. They showed that the variant 2760G>A and the -313G>A allele were associated with lymp node involvement (P=0.0062 and P=0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P=0.0012) and with progesterone negative tumors (P=0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Correlation of SIPA1 SNP rs3741378 with breast cancer susceptibility was also confirmed by Hsieh et al. |
| Bibliography |
| The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival. |
| Crawford NP, Walker RC, Lukes L, Officewala JS, Williams RW, Hunter KW. |
| Clin Exp Metastasis. 2008;25(4):357-69. Epub 2008 Feb 27. |
| PMID 18301994 |
| 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 MP. |
| Gene. 1998 Jul 3;214(1-2):215-21. |
| PMID 9651531 |
| Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and supcellular localization. |
| Farina A, Hattori M, Qin J, Nakatani Y, Minato N, Ozato K. |
| Mol Cell Biol. 2004 Oct;24(20):9059-69. |
| PMID 15456879 |
| Genetic variation in SIPA1 in relation to breast cancer risk and survival after breast cancer diagnosis. |
| Gaudet MM, Hunter K, Pharoah P, Dunning AM, Driver K, Lissowska J, Sherman M, Peplonska B, Brinton LA, Chanock S, Garcia-Closas M. |
| Int J Cancer. 2009 Apr 1;124(7):1716-20. |
| PMID 19089925 |
| Specific recruitment of SPA-1 to the immunological synapse: involvement of actin-bundling protein actinin. |
| Harazaki M, Kawai Y, Su L, Hamazaki Y, Nakahata T, Minato N, Hattori M. |
| Immunol Lett. 2004 Apr 15;92(3):221-6. |
| PMID 15081616 |
| Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression. |
| Hattori M, Tsukamoto N, Nur-e-Kamal MS, Rubinfeld B, Iwai K, Kubota H, Maruta H, Minato N. |
| Mol Cell Biol. 1995 Jan;15(1):552-60. |
| PMID 7799964 |
| Germline polymorphisms are potential metastasis risk and prognosis markers in breast cancer. |
| Hsieh SM, Lintell NA, Hunter KW. |
| Breast Dis. 2006-2007;26:157-62. (REVIEW) |
| PMID 17473374 |
| Distinct inherited metastasis susceptibility exists for different breast cancer suptypes: a prognosis study. |
| Hsieh SM, Look MP, Sieuwerts AM, Foekens JA, Hunter KW. |
| Breast Cancer Res. 2009;11(5):R75. |
| PMID 19825179 |
| Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility. |
| Hsieh SM, Smith RA, Lintell NA, Hunter KW, Griffiths LR. |
| BMC Cancer. 2009 Sep 18;9:331. |
| PMID 19765277 |
| 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 Jul;4(1):55-65. |
| PMID 12892713 |
| Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells. |
| Ishida D, Su L, Tamura A, Katayama Y, Kawai Y, Wang SF, Taniwaki M, Hamazaki Y, Hattori M, Minato N. |
| Immunity. 2006 Apr;24(4):417-27. |
| PMID 16618600 |
| Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice. |
| Ishida D, Yang H, Masuda K, Uesugi K, Kawamoto H, Hattori M, Minato N. |
| Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10919-24. Epub 2003 Sep 4. |
| PMID 12958214 |
| Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. |
| Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T. |
| Mol Cell Biol. 2000 Mar;20(6):1956-69. |
| PMID 10688643 |
| 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 Oct 15;66(20):9967-76. |
| PMID 17047059 |
| 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 Oct 31;272(44):28081-8. |
| PMID 9346962 |
| Spa-1 (Sipa1) and Rap signaling in leukemia and cancer metastasis. |
| Minato N, Hattori M. |
| Cancer Sci. 2009 Jan;100(1):17-23. Epub 2008 Nov 24. (REVIEW) |
| PMID 19037996 |
| Aquaporin-2 trafficking is regulated by PDZ-domain containing protein SPA-1. |
| Noda Y, Horikawa S, Furukawa T, Hirai K, Katayama Y, Asai T, Kuwahara M, Katagiri K, Kinashi T, Hattori M, Minato N, Sasaki S. |
| FEBS Lett. 2004 Jun 18;568(1-3):139-45. |
| PMID 15196935 |
| Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. |
| Park YG, Zhao X, Lesueur F, Lowy DR, Lancaster M, Pharoah P, Qian X, Hunter KW. |
| Nat Genet. 2005 Oct;37(10):1055-62. Epub 2005 Sep 4. |
| PMID 16142231 |
| Genomic sequencing reveals the structure of the Kcnk6 and map3k11 genes and their close vicinity to the sipa1 gene on mouse chromosome 19. |
| Saridaki A, Ferraz C, Demaille J, Scherer G, Roux AF. |
| Cytogenet Cell Genet. 2000;89(1-2):85-8. |
| PMID 10894943 |
| 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 Apr 25;278(17):15232-8. Epub 2003 Feb 15. |
| PMID 12590145 |
| Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. |
| Tsukamoto N, Hattori M, Yang H, Bos JL, Minato N. |
| J Biol Chem. 1999 Jun 25;274(26):18463-9. |
| PMID 10373454 |
| 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 Jan 1;39(1):66-73. |
| PMID 9027487 |
| Mutation analysis of SIPA1 in patients with juvenile myelomonocytic leukemia. |
| Yoshida N, Yagasaki H, Takahashi Y, Kudo K, Manabe A, Kojima S. |
| Br J Haematol. 2008 Sep;142(5):850-1. Epub 2008 May 19. |
| PMID 18492118 |
| Citation |
| This paper should be referenced as such : |
| Hattori, M |
| SIPA1 (signal-induced proliferation-associated 1) |
| Atlas Genet Cytogenet Oncol Haematol. 2011;15(2):214-216. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/SIPA1ID46282ch11q13.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jan 17 19:08:17 CET 2019 |
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