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SIPA1 (signal-induced proliferation-associated 1)

Written2010-05Masakazu Hattori
Laboratory of Host Defense, Department of Bioscience, Graduate School of Science, Kitasato University, Sagamihara, Kanagawa, 228-8555, Japan

(Note : for Links provided by Atlas : click)


Alias (NCBI)MGC102688
HGNC Alias symbSPA1
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 GRCh38/hg38-Dec_2013)  [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)


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.


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.


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

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.


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


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 ]

External links


HGNC (Hugo)SIPA1   10885
Entrez_Gene (NCBI)SIPA1    signal-induced proliferation-associated 1
GeneCards (Weizmann)SIPA1
Ensembl hg19 (Hinxton)ENSG00000213445 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000213445 [Gene_View]  ENSG00000213445 [Sequence]  chr11:65640121-65650920 [Contig_View]  SIPA1 [Vega]
ICGC DataPortalENSG00000213445
TCGA cBioPortalSIPA1
Genatlas (Paris)SIPA1
SOURCE (Princeton)SIPA1
Genetics Home Reference (NIH)SIPA1
Genomic and cartography
GoldenPath hg38 (UCSC)SIPA1  -     chr11:65640121-65650920 +  11q13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SIPA1  -     11q13.1   [Description]    (hg19-Feb_2009)
GoldenPathSIPA1 - 11q13.1 [CytoView hg19]  SIPA1 - 11q13.1 [CytoView hg38]
Genome Data Viewer NCBISIPA1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB005666 AF029789 AI307277 AK303551 AK308234
RefSeq transcript (Entrez)NM_006747 NM_153253
Consensus coding sequences : CCDS (NCBI)SIPA1
Gene ExpressionSIPA1 [ NCBI-GEO ]   SIPA1 [ EBI - ARRAY_EXPRESS ]   SIPA1 [ SEEK ]   SIPA1 [ MEM ]
Gene Expression Viewer (FireBrowse)SIPA1 [ Firebrowse - Broad ]
GenevisibleExpression of SIPA1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6494
GTEX Portal (Tissue expression)SIPA1
Human Protein AtlasENSG00000213445-SIPA1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96FS4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96FS4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96FS4
Domaine pattern : Prosite (Expaxy)PDZ (PS50106)    RAPGAP (PS50085)   
Domains : Interpro (EBI)PDZ    PDZ_sf    Rap/Ran-GAP_sf    Rap_GAP_dom   
Domain families : Pfam (Sanger)PDZ (PF00595)    Rap_GAP (PF02145)   
Domain families : Pfam (NCBI)pfam00595    pfam02145   
Domain families : Smart (EMBL)PDZ (SM00228)  
Conserved Domain (NCBI)SIPA1
AlphaFold pdb e-kbQ96FS4   
Human Protein Atlas [tissue]ENSG00000213445-SIPA1 [tissue]
Protein Interaction databases
IntAct (EBI)Q96FS4
Ontologies - Pathways
Ontology : AmiGOadaptive immune response  GTPase activator activity  GTPase activator activity  protein binding  nucleus  cytoplasm  cytosol  cytoskeleton organization  negative regulation of cell adhesion  signal transduction  protein C-terminus binding  membrane  transport vesicle  negative regulation of cell growth  protein-containing complex  intracellular signal transduction  cellular response to water deprivation  negative regulation of cell cycle  perinuclear region of cytoplasm  regulation of small GTPase mediated signal transduction  activation of GTPase activity  
Ontology : EGO-EBIadaptive immune response  GTPase activator activity  GTPase activator activity  protein binding  nucleus  cytoplasm  cytosol  cytoskeleton organization  negative regulation of cell adhesion  signal transduction  protein C-terminus binding  membrane  transport vesicle  negative regulation of cell growth  protein-containing complex  intracellular signal transduction  cellular response to water deprivation  negative regulation of cell cycle  perinuclear region of cytoplasm  regulation of small GTPase mediated signal transduction  activation of GTPase activity  
Pathways : KEGGRap1 signaling pathway    Leukocyte transendothelial migration   
REACTOMEQ96FS4 [protein]
REACTOME PathwaysR-HSA-392517 [pathway]   
NDEx NetworkSIPA1
Atlas of Cancer Signalling NetworkSIPA1
Wikipedia pathwaysSIPA1
Orthology - Evolution
GeneTree (enSembl)ENSG00000213445
Phylogenetic Trees/Animal Genes : TreeFamSIPA1
Homologs : HomoloGeneSIPA1
Homology/Alignments : Family Browser (UCSC)SIPA1
Gene fusions - Rearrangements
Fusion : QuiverSIPA1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSIPA1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SIPA1
Exome Variant ServerSIPA1
GNOMAD BrowserENSG00000213445
Varsome BrowserSIPA1
ACMGSIPA1 variants
Genomic Variants (DGV)SIPA1 [DGVbeta]
DECIPHERSIPA1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSIPA1 
ICGC Data PortalSIPA1 
TCGA Data PortalSIPA1 
Broad Tumor PortalSIPA1
OASIS PortalSIPA1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSIPA1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSIPA1
Mutations and Diseases : HGMDSIPA1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)SIPA1
DoCM (Curated mutations)SIPA1
CIViC (Clinical Interpretations of Variants in Cancer)SIPA1
NCG (London)SIPA1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SIPA1
NextProtQ96FS4 [Medical]
Target ValidationSIPA1
Huge Navigator SIPA1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDSIPA1
Pharm GKB GenePA35785
Clinical trialSIPA1
DataMed IndexSIPA1
PubMed47 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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