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Gene Section
Mini Review
HAS2 (hyaluronan synthase 2)
Diogo Escudero
University of Miami School of Medicine, Miami, Florida 33136, USA (DE)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/HAS2ID412ch8q24.html
DOI: 10.4267/2042/44682
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
embedded HA synthases, although HAS2 is the only
essential gene. The isozymes are coded by 3 separate
genes that, although related, are unlinked in the
chromosome. Regulation occurs at trans-cription, posttranslational levels, as well as, by alternative splicing,
differential sub-cellular locali-zation and epigenetic
processes. Hyaluronan deposits in the extracellular
matrix have been associated with a variety of cellular
processes such as motility, adhesion, division,
morphogenesis, wound healing and vascular
development. HAS2 overexpression, as well as,
amplification of locus 8q24.12, has been implicated in
tumor proliferation and metastasis in genitourinary
tumors. Recently, the degree to which HA synthases
can overexpressed has suggested the likelihood the
gene may play contradicting roles as tumor suppressor
and oncogene.
Identity
Other names: MGC126241; MGC126242
HGNC (Hugo): HAS2
Location: 8q24.13
Note
HA Synthase 2 was first cloned in 1996 by Watanabe
and Yamaguchi. The following year, Spicer et al.
identified and localized the human HAS2 gene to
chromosome 8q24.12.
DNA/RNA
Note
Three independently expressed hyaluronan synthase
genes have been identified in the human genome.
HAS2 is present in chromosome 8q24.12, while HAS1
and HAS3 have been identified to loci 19q13.4 and
16q22.1 respectively.
Protein
Note
HAS2, a member of the glycosyl transferase family 2
proteins, is a multipass transmembrane protein that
catalyses the polymerization of the integral
extrecellular matrix component Hyaluronic acid from
intracellular UDP-esterified precursor, resul-ting in
glucuronic acid and N-acetylglucosamine dissacharide
motifs.
Description
The HAS2 gene encodes for a 552 amino acid product
comprised of 4 exons. Translation starts at the first
nucleotide of exon 2 while a discrete 5'-untranslated
region (UTR) is formed in exon 1.
Transcription
Hyaluronan is catalyzed by three membrane-
HAS2 gene presented in the minus strand of chromosome 8.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2)
121
HAS2 (hyaluronan synthase 2)
Escudero D
Illustration of HAS multipass transmembrane isozymes and their products.
protein family and catalyses the addition of UDPesterified residues, to form
glucuronic acid and N-acetylglucosamine dissacha-ride
motifs present in HA molecules. Interactions between
plasma membrane embedded HA receptors with
hyaluronan in the cellular matrix have been suggested
to either induce or repress HAS2's catalytic activity.
The presence of hyaluronan in the extracellular matrix
has been linked to a great number of vital cellular
processes such cell division, motility and
morphogenesis, among many others. HAS2 is either an
oncogene or a tumor suppressor depending on the
concentration and length of HA products deposited in
the extracellular matrix. Long HA chains of high
molecular weight in high concentrations have been
linked with supressing angiogenesis and tumor
proliferation, whereas 2-3 fold HAS2 overexpression
has been implicated in the proliferation and metastasis
in various genitourinary tumor types.
Description
HAS2 is one of the three characterized HA synthases
responsible for the polymerization of Hyaluronic Acid
in the extracellular matrix and is the only essential gene
of the family. Although all three isozymes are equally
capable of synthesizing HA polymers, it has been
shown that HAS2 is the main HA synthase
polymerizing long hyaluronan chains of MW ~2x106
Daltons.
Expression
The extent of HAS2 expression and catalytic activity
has been linked to specific interactions between the
extracellular hyaluronan and the HA receptors, CD44
and RHAMM, distributed in the plasma membrane.
The underlying signaling pathways regulating HAS2
expression have not been fully characterized. A number
of distinctively regulated factors have been associated
with HA deposition and HAS2 expression such as IL1beta, NF-kappaB, all-trans-Retinoic Acid, SP1, Ras,
TGF-beta1 among many others.
Homology
A total of 3 mammalian HAS genes have been isolated
and identified (HAS1, HAS2, HAS3). Although they
share similar amino acid sequences and structural
conformations, each isozyme present different spacial
and temporal expression patterns, molecular stability,
kinetic properties and ability of yielding hyaluronan
chains different in length and concentration.
Localisation
HAS2 is localized in the plasma membrane as a
multipass transmembrane protein. Although it has been
suggested the human HAS2 may share the same
proposed topological domains as its bacterial
counterpart, the extent to which this statement trully
represents its actual architecture has not yet been
shown.
Mutations
Function
Note
Developmental studies have described mutations
disrupting HAS2 synthesis as embryonic lethal. Such
Hyaluronan synthase 2 is responsible for the synthesis
and deposition of hyaluronan in the extracellular
matrix. HAS2 is a member of the glycosyl transferase 2
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2)
122
HAS2 (hyaluronan synthase 2)
Escudero D
mutations prevent cardiac endothelial to mesenchymal
transition, resulting in failed heart morphogenesis.
of HA have been observed in vascular diseases such as
atherosclerosis, restenotic lesion.
Prognosis
Increasing severity in athrosclerosis has been linked
with decreasing concentration of hyaluronan
distribution. Yet, the role HA may be playing during
earlier phases of the disease is yet to be determined due
to difficulty in early detection of the disease. Decreased
HAS2 activity is stipulated to be playing a possible role
in this matter.
Implicated in
Various cancer
Note
Studies dating over 50 years have suggested an
association between the increasing deposition of HA
and tumors. Because hyaluronan is associated with
such a variety of important biological cellular
processes, it has been suggested that the abnormal
overexpression of HAS2, among the other HA
synthases, as well as deposition of HA in the
extracellular matrix account for hijacked pathways to
stimulate cell growth, proliferation, angiogenesis and
metastasis in cancer cells. The use of pharmacological
agents affecting HAS2 activity, as well as, HA
breakdown in cancer treatment are promising. Recent
studies suggest that tumor cells become less aggressive
and proliferative when HA synthase is being
suppressed or overexpressed in high concentrations.
Diagnostic tests have been developed assaying for
concentration of deposited hyaluronan as a tumor
marker. The HA-Hase test, for example, is a sensitive
and accurate diagnostic test for bladder cancer
measuring the concentrations of hyaluronan and
hyaluronidase (HA degrading protein) present in urine
samples.
Disease
Dysfunctional expression of HAS2 has been published
in many genitourinary tumors, such as prostate cancer,
testicular cancer and bladder cancer. This altered
expression has been linked with chromosomal locus
8q24 amplification as well as deregulated HAS2
transcription, which have been shown to follow tumor
progression.
Prognosis
Histological studies, using specific hyaluronan affinity
probes, suggest that all human epithelial tumors are
associated with elevated amounts of hyaluronan in the
extracellular matrix. Consequen-tly, overexpression of
HAS2 has been observed in various types of cancer.
The presence of tumor associated hyaluronan has been
observed in prostate cancer cells of high Gleason scores
and matastasis, indicating poor prognosis. Also,
primary tumor invasiveness and elevated PSA
recurrence after surgical tumor removal have been
correlated with strong stromal hyaluronan staining in
radical prostatectomy specimens.
References
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M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y,
Miyauchi S, Spicer AP, McDonald JA, Kimata K. Three
isoforms of mammalian hyaluronan synthases have distinct
enzymatic
properties.
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This article should be referenced as such:
Vascular disease
Escudero D. HAS2 (hyaluronan synthase 2). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(2):121-123.
Disease
Changes in the concentration and cellular distribu-tion
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2)
123