Download Gene Section SIPA1 (signal induced proliferation associated 1)

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Gene Section
Review
SIPA1 (signal-induced proliferation-associated 1)
Masakazu Hattori
Laboratory of Host Defense, Department of Bioscience, Graduate School of Science, Kitasato University,
Sagamihara, Kanagawa, 228-8555, Japan (MH)
Published in Atlas Database: May 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/SIPA1ID46282ch11q13.html
DOI: 10.4267/2042/44969
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: MGC102688, MGC17037, SPA1
HGNC (Hugo): SIPA1
Location: 11q13.1
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.
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.
Expression
SPA-1
is
most
abundantly
expressed
in
lymphohematopoietic tissues including bone marrow,
thymus and spleen.
Localisation
Description
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.
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.
Function
Transcription
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 extra-
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.
Structure of the SIPA1 gene.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
214
SIPA1 (signal-induced proliferation-associated 1)
Hattori M
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.
cellular 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-1like (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 agedependent progression of T-cell unresponsiveness,
preceding the overt development of leukemia described
as follows. Such Spa-1-/- T cells show defective Rasmediated ERK activation in response to TCRstimulation. 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 Spa1-/- 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
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
Implicated in
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.
215
SIPA1 (signal-induced proliferation-associated 1)
Hattori M
Noda Y, Horikawa S, Furukawa T, Hirai K, Katayama Y, Asai
T, Kuwahara M, Katagiri K, Kinashi T, Hattori M, Minato N,
Sasaki S. Aquaporin-2 trafficking is regulated by PDZ-domain
containing protein SPA-1. FEBS Lett. 2004 Jun 18;568(13):139-45
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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
This article should be referenced as such:
Hattori M. SIPA1 (signal-induced proliferation-associated 1).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2):214-216.
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