Download Gene Section ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))

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Gene Section
Review
ERBB3 (v-erb-b2 erythroblastic leukemia viral
oncogene homolog 3 (avian))
Smita Awasthi, Anne W Hamburger
University of Maryland School of Medicine, Department of Pathology and University of Maryland
Greenebaum Cancer Center, USA (SA, AWH)
Published in Atlas Database: May 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/ERBB3ID40479ch12q13.html
DOI: 10.4267/2042/48356
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
through. At least three of these transcripts code for
truncated, secreted soluble forms of ERBB3 (Lee and
Maihle, 1998).
Identity
Other names: ErbB-3, HER3, LCCS2, MDA-BF-1, cerbB-3, c-erbB3, erbB3-S, p180-ErbB3, p45-sErbB3,
p85-sErbB3
HGNC (Hugo): ERBB3
Location: 12q13.2
Pseudogene
None reported.
Protein
DNA/RNA
Description
Description
The ERBB3 gene encodes a member of the epidermal
growth factor receptor (EGFR) family of receptor
tyrosine kinases.
The 6.2 kb transcript encodes a 148 kDa protein which
is post-translationally glycosylated to yield a protein of
180 kDa (Kraus et al., 1989).
The extracellular ligand-binding domain consists of
four subdomains that change conformation in response
to ligand.
Domains I and III bind NRG with high affinity (Cho
and Leahy, 2002). Due to substitutions in the kinase
domain at aa 740, 759 and 834, ErbB3 lacks potent
tyrosine kinase activity.
However, recent data indicate that ErbB3 maintains
some autophosphorylation activity (Shi et al., 2010).
Heterodimerization with other ErbB family members,
most notably ErbB2, is needed to convey biological
signals through phosphorylation of downstream
substrates, most notably AKT (Olayioye et al., 2000).
In general, activation of these pathways leads to cell
proliferation or differentiation.
Alternate transcriptional splice variants encoding
different isoforms have been characterized.
The ERBB3 gene, which maps to human chromosome
12q13.2, is 23.2 kb in size and consists of 28 exons.
The gene for the extracellular ligand binding domain of
ErbB3 has 43-45% homology with EGFR and ERBB2
and 56-67% homology with ERBB4.
The cytoplasmic tyrosine kinase domain sequences
have 60-63% homology with those of the other ErbB
receptors (Kraus et al., 1989).
Transcription
The ERBB3 promoter region is GC rich (65%) and,
like EGFR, does not contain a TATA box. A proximal
promoter was observed within 600 bp flanking Exon1.
AP2-1 (OB2-1) and Fox3a have been demonstrated to
be functional transcriptional regulators at upstream start
sites (Skinner and Hurst, 1993). A Sox10 regulated
enhancer has been identified at chr12:5476306554763421 in neural crest derived cells. The human
ERBB3 gene is transcribed as a 6.2 kb message of 4080
nucleotides and 1342 codons specifying the full-length
protein. There are four additional alternate transcripts
of 1.6, 1.7, 2.1 and 2.3 kb generated by intron read
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
871
ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))
Awasthi S, Hamburger AW
The alignment of ERBB3 mRNA to its genomic sequence.
Linear schematic of ErbB3. Functional domains, including Signal Peptide (SP), the Ligand Binding Domain (LBD) with four subdomains
(indicated by the red lines) transmembrane domain (TM), tyrosine kinase domain (TKD), and C-terminal signaling domain (SD).
Each alternate transcript encodes a truncated form of
the ligand-binding domain of ErbB3 and can compete
for binding with ligand, resulting in growth inhibition
(Lee et al., 2001).
ErbB3 is post translationally regulated by a variety of
mechanisms. After ligand binding, it is phosphorylated
on 14 tyrosine residues by other ErbB family members
(Kim et al., 1998) and under some circumstance c-Src,
Met and BRK.
Protein levels are regulated by the E3 ligase Nrdp1 and
the Nrdp1 regulator USP8.
USP8 itself is regulated by AKT, suggesting a feedback
mechanism for ErbB activity (Wu et al., 2004).
also localized to the nucleus (Offterdinger et al., 2002).
Function
Activation and interactions
ErbB3 when localized at the plasma membrane binds
different forms of neuregulin. The NRG family consists
of a large group of isoforms, encoded by four genes
with an EGF like C terminal portion and a variable N
terminal
region.
Ligand
binding
leads
to
heterodimerization preferentially with ErbB2, but also
other ErbB family members in secondary reactions
(Pinkas-Kramarski et al., 1996). The transmembrane
domain, which binds EBP1, is important for dimer
stabilization (Jura et al., 2009). The cytoplasmic
domain lacks potent tyrosine kinase activity. However,
this domain has been shown to be an allosteric activator
of the ErbB2 kinase domain (Zhang et al., 2006). The
cytoplasmic tail of ErbB3 is phosphorylated by ErbB2
and is a signaling substrate. The 14 phosphorylated
tyrosines in the C terminal signaling tail of ErbB3 can
potentially dock numerous SH2/3 or PTB binding
proteins involved in different biological pathways
(Hynes and Lane, 2005).
Signaling and cellular activity
In contrast to other ErbB proteins, ErbB3 is not
transforming when overexpressed or constitutively
activated (Alimandi et al., 1995). Once phosphorylated
Expression
ErbB3 is widely expressed in embryonic and adult
tissues.
It is expressed in epithelial cells of the gastrointestinal,
respiratory, reproductive and urinary tracts as well as
the skin and endocrine systems. It is highly expressed
in neuronal tissue. Expression is relatively low in cells
of the hematopoietic and immune systems (Kraus et al.,
1989; Prigent et al., 1992).
Localisation
ErbB3 is generally located in the plasma membrane.
However, more recent studies indicate that ErbB3 is
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
872
ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))
by other ErbB family members or Src, Met or BRK,
ErbB-3 can then bind numerous other signaling
proteins. Activation of the PI-3
kinase-AKT pathway is especially important as there
are six docking sites for the p85 subunit of PI-3K in the
ErbB3 cytoplasmic tail at Tyr 1035, 1178, 1203/1205,
1257 and 1270. AKT regulates many downstream
signaling nodes, in particular the two mTOR containing
complexes. ErbB3 can also activate the MAPK
pathway via its interactions with Grb7 (Tyr 1180,1243)
and SHC (1309) (Hynes and Lane, 2005). Thus, ErbB3
is important in biological processes such as translation,
apoptosis, nutrient sensing, metabolic regulation,
angiogenesis and cell cycle control. Increased
expression or activity of ErbB3 has been associated
with resistance to EGFR and ErbB2 inhibitors (Sergina
et al., 2007) and hormonal therapies (Liu et al., 2007).
ErbB3 when localized in the nucleus acts as a
transcription factor to regulate Cyclin D1 and β-casein
genes (Andrique et al., 2012).
Physiological
ErbB3 knock-out mice die by E13.5 with defective
heart valve formation, but normal heart trabeculation.
The animals show a generalized neural crest defects
and lack Schwann cell precursors (Erickson et al.,
1997). Due to the importance of ErbB3 in breast
cancer, the role of ErbB3 in mammary development
has been well-studied. ErbB3 is required for ductal
morphogenesis in the mouse mammary gland (Stern,
2003). ErbB3 has also been implicated in maintenance
of the luminal epithelial subtype in the breast (Balko et
al., 2012).
Awasthi S, Hamburger AW
The other mutation was a silent mutation in exon 21
(2484 T > C) (His828His) detected in an invasive
ductal carcinoma of the breast (2% of the total 60
breast cancers) (Jeong et al., 2006).
Implicated in
Breast cancer
Prognosis
Increased expression of ErbB3 in breast cancer cells
relative to normal epithelium is common. The increased
expression is not due to genomic amplification
(Gasparini et al., 1994). High ErbB3 expression has
been correlated with both increased and poorer survival
(Hamburger, 2008). The ErbB2/3 heterodimer is
essential for proliferation of malignant mammary
epithelial cells (Holbro et al., 2003). ErbB3 contributes
to tamoxifen resistance (Liu et al., 2007) and activation
of ErbB3 is also associated with resistance to ErbB
directed tyrosine kinase inhibitors (Sergina et al.,
2007).
Ovarian cancer
Prognosis
Genomic amplification of ErbB3 has been noted in
ovarian cancer and ErbB3 overexpression is associated
with poor survival (Wilken et al., 2012). Truncated
ErbB3 transcripts that code for soluble truncated
proteins have been observed in ovarian cancer cell
lines. Such soluble forms can inhibit proliferation
(Maihle 2001). These soluble forms may have potential
as markers of disease progression.
Homology
Prostate cancer
The ErbB family has evolved from a single ligandreceptor combination in C. elegans (let-23 28% aa
similarity) through Drosophila with one receptor
(EGFR, 39% similarity) and four ligands to vertebrates,
where four ErbB receptor bind multiple EGF-related
ligands. The ERBB3 gene is conserved in chimpanzee
(99% similarity), dog, cow, mouse (90%), rat, chicken,
and zebrafish.
Prognosis
Increased expression of ErbB3 has been noted in
prostate cancer (Cheng et al., 2007; Koumakpayi et al.,
2006). Activation of the ErbB2/3 heterodimer stabilizes
Androgen Receptor contributing to hormone
independent growth (Mellinghoff et al., 2004). NRG
can activate the EBP1 Protein leading to decreased AR
activity (Zhang and Hamburger, 2005). Nuclear
localization of ErbB3 has been associated with both
poorer and better prognoses. A secreted ErbB3 isoform
has been shown to enhance bone metastasis (Chen et
al., 2007).
Mutations
Germinal
An A to G mutation is noted in intron 10 in Lethal
Congential Contracture Syndrome 2 (LCCS2). LCCS2
is an autosomal recessive neurogenic form of a
neonatally lethal arthrogryposis that is associated with
atrophy of the anterior horn of the spinal cord (Narkis
et al., 2004).
Pancreatic cancer
Somatic
Lung cancer
Mutations in ErbB3 have been rarely noted in cancer.
One of the 2 mutations reported was a missense
mutation in exon 21 (2537 G > T) (Ser846Ile) detected
in a rectal mucinous adenocarcinoma (1% of the total
colon cancer samples.
Prognosis
Overexpression of ErbB3 generally correlates with
poor prognosis (Yi et al., 1997). Several studies have
indicated that ErbB3 affects clinical responsiveness to
tyrosine kinase inhibitors. Cell lines with wild type and
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12)
Prognosis
ErbB3 mRNA and protein has consistently been
observed to be increased and associated with poor
outcome (Friess et al., 1995).
873
ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))
cerebellar and cardiac development: a comparison with ErbB2and
heregulin-deficient
mice.
Development.
1997
Dec;124(24):4999-5011
high levels of ErbB3 respond better to EGFR inhibitors
(Engelman et al., 2005). In addition, gefitinib resistant
NCSLC cells can amplify MET which then
phosphorylates and activates ErbB3 and AKT pathways
(Engelman et al., 2007). ErbB3 has also been
implicated in inhibition of apoptosis in lung cancer cell
lines (Sithanandam et al., 2005).
Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW,
Younes M, Cagle PT. High c-erbB-3 protein expression is
associated with shorter survival in advanced non-small cell
lung carcinomas. Mod Pathol. 1997 Feb;10(2):142-8
Kim HH, Vijapurkar U, Hellyer NJ, Bravo D, Koland JG. Signal
transduction by epidermal growth factor and heregulin via the
kinase-deficient ErbB3 protein. Biochem J. 1998 Aug 15;334 (
Pt 1):189-95
Schizophrenia
Prognosis
The NRG1 gene was identified as a potential
susceptibility gene for schizophrenia and defects in the
expression of ErbB3 were also shown to occur in the
prefrontal cortex of schizophrenic patients. However,
currently the association between ErbB3 expression
and schizophrenia is unclear (Corfas et al., 2004).
Lee H, Maihle NJ. Isolation and characterization of four
alternate c-erbB3 transcripts expressed in ovarian carcinomaderived cell lines and normal human tissues. Oncogene. 1998
Jun 25;16(25):3243-52
Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB
signaling network: receptor heterodimerization in development
and cancer. EMBO J. 2000 Jul 3;19(13):3159-67
Diabetes
Lee H, Akita RW, Sliwkowski MX, Maihle NJ. A naturally
occurring secreted human ErbB3 receptor isoform inhibits
heregulin-stimulated activation of ErbB2, ErbB3, and ErbB4.
Cancer Res. 2001 Jun 1;61(11):4467-73
Prognosis
Genome-wide association studies have identified
associations between type I diabetes and singlenucleotide polymorphisms (SNP) at chromosome
12q13 surrounding the ERBB3 gene. The most
significant association was observed with a SNP in
exon 27 of the ERBB3 gene and an intergenic SNP
(Keene et al., 2012). In addition, ErbB3 has been
demonstrated to modulate antigen presenting cell
function and type I diabetes risk (Jing et al., 2011).
Cho HS, Leahy DJ. Structure of the extracellular region of
HER3 reveals an interdomain tether. Science. 2002 Aug
23;297(5585):1330-3
Offterdinger M, Schöfer C, Weipoltshammer K, Grunt TW. cerbB-3: a nuclear protein in mammary epithelial cells. J Cell
Biol. 2002 Jun 10;157(6):929-39
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd,
Hynes NE. The ErbB2/ErbB3 heterodimer functions as an
oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell
proliferation. Proc Natl Acad Sci U S A. 2003 Jul
22;100(15):8933-8
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Awasthi S, Hamburger AW
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