Download Gene Section IGFBP6 (insulin-like growth factor binding protein 6)

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Gene Section
Short Communication
IGFBP6 (insulin-like growth factor binding
protein 6)
Leon A Bach
Department of Endocrinology and Diabetes, Alfred Hospital and Department of Medicine (Alfred),
Monash University, Melbourne 3004, Australia (LAB)
Published in Atlas Database: April 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/IGFBP6ID40933ch12q13.html
DOI: 10.4267/2042/55372
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on IGFBP6, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
Other names: IBP6
HGNC (Hugo): IGFBP6
Location: 12q13.13
DNA/RNA
Description
Structure of the C-terminal domain of human IGFBP-6
(Headey et al., 2004; Bach et al., 2013).
The size of the IGFBP6 gene is 4.91 kb and it
contains 4 exons (Thierry-Mieg and Thierry-Mieg,
2006).
It consists of 3 domains: the N- and C-terminal
domains, which contain internal disulfide bonds,
are joined by a linker domain. It contains 8
disulfide bonds, 5 in the N-terminal IGFBP domain
and 3 in the C-terminal domain (Neumann et al.,
1998; Neumann and Bach, 1999). Of these, the first
3 N-terminal disulfides are unique, whereas the
remaining 2 N-terminal and 3 C-terminal disulfides
are homologous with other IGFBPs. A peptide
based on the N-terminal subdomain is largely
unstructured (Chandrashekaran et al., 2007),
whereas the IGF binding subdomain is conserved
with other IGFBPs. Human IGFBP-6 is Oglycosylated on 5 Ser/Thr residues within the linker
domain, which has a distinct sequence from other
IGFBPs (Bach et al., 1992; Neumann et al., 1998).
The C-terminal domain contains a thyroglobulin
Transcription
One 1175 bp transcript encodes the full-sized 240
amino acid protein.
Smaller transcripts sized 597, 705 and 463 bp may
be incomplete and putatively encode fragments
containing 51-140 amino acids (Thierry-Mieg and
Thierry-Mieg, 2006).
Protein
Description
IGFBP-6 belongs to the insulin-like growth factor
binding protein family.
It is expressed as a 240 amino acid proprotein, and
processed to a 213-216 amino acid mature protein.
Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1)
15
IGFBP6 (insulin-like growth factor binding protein 6)
Bach LA
other proteins containing a thyroglobulin type 1
fold.
IGFBP-6 is found in mammalian species including
man, cow, rat and mouse, as well as trout and
salmon. The IGFBP6 gene is duplicated in
zebrafish, and each gene has a distinct expression
pattern; however, overexpression of either gene
inhibits embryonic growth and development (Wang
et al., 2009).
type 1 fold (Headey et al., 2004), which is also true
for other IGFBPs, and a functional nuclear
localization sequence (Iosef et al., 2008).
Expression
IGFBP6 is widely expressed in human tissues, with
low levels of transcripts found in most tissues.
Expression is highest in smooth muscle, olfactory
bulb, ganglia, retina and the atrioventricular node
(Wu et al., 2013). IGFBP6 is also found in many
body fluids, including serum, cerebrospinal fluid,
amniotic fluid, and follicular fluid (Baxter and
Saunders, 1992; Bach, 1999; Kolker et al., 2012).
IGFBP6 expression is regulated in a cell-specific
manner by cAMP, IGFs, retinoic acid, vitamin D,
glucocorticoids, p53, beta-catenin, hedgehog, TGFbeta and SEMA3B (Bach et al., 2013).
Implicated in
Various cancers
Note
In many studies, IGFBP-6 expression is lower in
(1) malignant vs normal cells; and (2) metastatic vs
primary tumors, suggesting that it has an inhibitory
effect on tumor development, at least in part by
inhibiting IGF actions. Examples include
rhabdomyosarcoma, head and neck cancer, lung
cancer and gastric cancer (Bach et al., 2013).
Exogenously added or overexpressed IGFBP-6
inhibits rhabdomyosarcoma and neuroblastoma
xenograft growth in mice (Grellier et al., 1998;
Gallicchio et al., 2001). IGFBP6 has been
implicated as a tumor suppressor in nasopharyngeal
cancer by its role as a transcription factor for EGR1 (Kuo et al., 2010).
Localisation
Predominantly extracellular. Nuclear localization
via a C-domain nuclear localization signal that
binds importin-a has also been reported (Iosef et al.,
2008).
Function
Unlike other IGFBPs, IGFBP-6 has a ~50-fold
binding preference for IGF-II over IGF-I. It
therefore is a relatively specific inhibitor of IGF-II
actions (Bach, 1999; Bach, 2005; Bach et al.,
2013). It is antiproliferative and proapoptotic in a
number of cell lines in vitro (Bach, 1999; Bach,
2005; Bach et al., 2013). At least some of its
actions in regulating cell fate are mediated by
interaction with Ku80, a DNA-end binding protein
(Iosef et al., 2010). IGFBP-6 has also been reported
to have IGF-independent actions, such as
promotion of cancer cell migration an IGFindependent mechanism that involves binding
prohibitin-2 (Fu et al., 2007; Fu et al., 2013) and
angiogenesis (Zhang et al., 2012). It has been
reported to be a tumor suppressor in
nasopharyngeal cancer through regulation of EGR1 expression (Kuo et al., 2010).
As well as binding IGFs with high affinity, IGFBP6 also binds other unrelated proteins, including
importin-α, prohibitin-2 and Ku80 as described
above. Other proteins that bind IGFBP-6 inhibits
osteoblast differentiation, which may be mediated
by binding to LIM mineralization protein-1 (LMP1) (Strohbach et al., 2008), the vitamin D receptor
(Cui et al., 2011), and the thyroid hormone-α
receptor (Qiu et al., 2012).
Global deletion of IGFBP6 expression does not
result in a major phenotype, presumable because of
functional redundancy with other IGFBPs.
Chronic renal failure
Note
Circulating IGFBP-6 levels are increased in patients
with chronic renal failure (Powell et al., 1997; Van
Doorn et al., 1999) and this, together with increased
levels of other IGFBPs, may contribute to impaired
IGF action in these patients.
Proliferative vitreoretinopathy
Note
IGFBP-6 levels are increased in serum and vitreous
from patients with this condition, and serum levels
decreased after vitrectomy (Yu et al., 2014).
Non islet-cell tumor hypoglycemia
Note
This rare condition is due to overexpression by
tumors of a partially processed form of IGF-II that
does not form normal serum complexes with
IGFBPs and the acid-labile subunit and therefore
has increased bioavailability. IGFBP-6 levels are
increased in this condition (Van Doorn et al., 1999).
References
Homology
Bach LA, Thotakura NR, Rechler MM. Human insulin-like
growth factor binding protein-6 is O-glycosylated. Biochem
Biophys Res Commun. 1992 Jul 15;186(1):301-7
IGFBP-6 shares homology with IGFBPs 1-5 in its
N-terminal IGF binding domain and its C-terminal
domain. It shares homology in its C-domain with
Baxter RC, Saunders H. Radioimmunoassay of insulin-like
growth factor-binding protein-6 in human serum and other
body fluids. J Endocrinol. 1992 Jul;134(1):133-9
Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1)
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IGFBP6 (insulin-like growth factor binding protein 6)
Bach LA
Powell DR, Liu F, Baker BK, Hintz RL, Durham SK, Brewer
ED, Frane JW, Tonshoff B, Mehls O, Wingen AM, Watkins
SL, Hogg RJ, Lee PD. Insulin-like growth factor-binding
protein-6 levels are elevated in serum of children with
chronic renal failure: a report of the Southwest Pediatric
Nephrology Study Group. J Clin Endocrinol Metab. 1997
Sep;82(9):2978-84
Strohbach C, Kleinman S, Linkhart T, Amaar Y, Chen ST,
Mohan S, Strong D. Potential involvement of the
interaction between insulin-like growth factor binding
protein (IGFBP)-6 and LIM mineralization protein (LMP)-1
in regulating osteoblast differentiation. J Cell Biochem.
2008 Aug 1;104(5):1890-905
Wang X, Lu L, Li Y, Li M, Chen C, Feng Q, Zhang C, Duan
C. Molecular and functional characterization of two distinct
IGF binding protein-6 genes in zebrafish. Am J Physiol
Regul Integr Comp Physiol. 2009 May;296(5):R1348-57
Grellier P, De Galle B, Babajko S. Expression of insulinlike growth factor-binding protein 6 complementary DNA
alters neuroblastoma cell growth. Cancer Res. 1998 Apr
15;58(8):1670-6
Iosef C, Vilk G, Gkourasas T, Lee KJ, Chen BP, Fu P,
Bach LA, Lajoie G, Gupta MB, Li SS, Han VK. Insulin-like
growth factor binding protein-6 (IGFBP-6) interacts with
DNA-end binding protein Ku80 to regulate cell fate. Cell
Signal. 2010 Jul;22(7):1033-43
Neumann GM, Marinaro JA, Bach LA. Identification of Oglycosylation sites and partial characterization of
carbohydrate structure and disulfide linkages of human
insulin-like growth factor binding protein 6. Biochemistry.
1998 May 5;37(18):6572-85
Bach LA. Insulin-like growth factor binding protein-6: the
"forgotten" binding protein? Horm Metab Res. 1999 FebMar;31(2-3):226-34
Kuo YS, Tang YB, Lu TY, Wu HC, Lin CT. IGFBP-6 plays
a role as an oncosuppressor gene in NPC pathogenesis
through regulating EGR-1 expression. J Pathol. 2010
Nov;222(3):299-309
Neumann GM, Bach LA. The N-terminal disulfide linkages
of human insulin-like growth factor-binding protein-6
(hIGFBP-6) and hIGFBP-1 are different as determined by
mass spectrometry. J Biol Chem. 1999 May
21;274(21):14587-94
Cui J, Ma C, Qiu J, Ma X, Wang X, Chen H, Huang B. A
novel interaction between insulin-like growth factor binding
protein-6 and the vitamin D receptor inhibits the role of
vitamin D3 in osteoblast differentiation. Mol Cell
Endocrinol. 2011 May 16;338(1-2):84-92
Van Doorn J, Ringeling AM, Shmueli SS, Kuijpers MC,
Hokken-Koelega AC, van Buul-Offers SC, Jansen M.
Circulating levels of human insulin-like growth factor
binding protein-6 (IGFBP-6) in health and disease as
determined by radioimmunoassay. Clin Endocrinol (Oxf).
1999 May;50(5):601-9
Kolker E, Higdon R, Haynes W, Welch D, Broomall W,
Lancet D, Stanberry L, Kolker N. MOPED: Model
Organism Protein Expression Database. Nucleic Acids
Res. 2012 Jan;40(Database issue):D1093-9
Qiu J, Ma XL, Wang X, Chen H, Huang BR. Insulin-like
growth factor binding protein-6 interacts with the thyroid
hormone receptor α1 and modulates the thyroid hormoneresponse in osteoblastic differentiation. Mol Cell Biochem.
2012 Feb;361(1-2):197-208
Gallicchio MA, Kneen M, Hall C, Scott AM, Bach LA.
Overexpression of insulin-like growth factor binding
protein-6 inhibits rhabdomyosarcoma growth in vivo. Int J
Cancer. 2001 Dec 1;94(5):645-51
Zhang C, Lu L, Li Y, Wang X, Zhou J, Liu Y, Fu P,
Gallicchio MA, Bach LA, Duan C. IGF binding protein-6
expression in vascular endothelial cells is induced by
hypoxia and plays a negative role in tumor angiogenesis.
Int J Cancer. 2012 May 1;130(9):2003-12
Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P,
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growth factor (IGF) binding protein-6: structure and
interaction
with
IGF-II.
Mol
Endocrinol.
2004
Nov;18(11):2740-50
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protein-6 and cancer. Clin Sci (Lond). 2013
Feb;124(4):215-29
Bach LA. IGFBP-6 five years on; not so 'forgotten'? Growth
Horm IGF Res. 2005 Jun;15(3):185-92
Thierry-Mieg
D,
Thierry-Mieg
J.
AceView:
a
comprehensive cDNA-supported gene and transcripts
annotation. Genome Biol. 2006;7 Suppl 1:S12.1-14
Fu P, Yang Z, Bach LA. Prohibitin-2 binding modulates
insulin-like growth factor-binding protein-6 (IGFBP-6)induced rhabdomyosarcoma cell migration. J Biol Chem.
2013 Oct 11;288(41):29890-900
Chandrashekaran IR, Yao S, Wang CC, Bansal PS,
Alewood PF, Forbes BE, Wallace JC, Bach LA, Norton RS.
The N-terminal subdomain of insulin-like growth factor
(IGF) binding protein 6. Structure and interaction with
IGFs. Biochemistry. 2007 Mar 20;46(11):3065-74
Wu C, Macleod I, Su AI. BioGPS and MyGene.info:
organizing online, gene-centric information. Nucleic Acids
Res. 2013 Jan;41(Database issue):D561-5
Yu J, Peng R, Chen H, Cui C, Ba J, Wang F. Kininogen 1
and insulin-like growth factor binding protein 6: candidate
serum biomarkers of proliferative vitreoretinopathy. Clin
Exp Optom. 2014 Jan;97(1):72-9
Fu P, Thompson JA, Bach LA. Promotion of cancer cell
migration: an insulin-like growth factor (IGF)-independent
action of IGF-binding protein-6. J Biol Chem. 2007 Aug
3;282(31):22298-306
This article should be referenced as such:
Iosef C, Gkourasas T, Jia CY, Li SS, Han VK. A functional
nuclear localization signal in insulin-like growth factor
binding
protein-6
mediates
its
nuclear
import.
Endocrinology. 2008 Mar;149(3):1214-26
Atlas Genet Cytogenet Oncol Haematol. 2014; 19(1)
Bach LA. IGFBP6 (insulin-like growth factor binding protein
6). Atlas Genet Cytogenet Oncol Haematol. 2015;
19(1):15-17.
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