IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)

2010-11-01   Theoni Trangas , Panayotis Ioannidis 

Department of Biological Applications, Technologies University of Ioannina, Ioannina, Greece (TT); National Reference Center for Mycobacteria, Sotiria Hospital, Athens, Greece (PI)

Identity

HGNC
LOCATION
17q21.32
IMAGE
Atlas Image
LOCUSID
ALIAS
CRD-BP,CRDBP,IMP-1,IMP1,VICKZ1,ZBP1
FUSION GENES

DNA/RNA

Atlas Image

Description

There are 4 probable alternative promoters driving transcription of IGF2BP1 and two of them have been experimentally confirmed (Gu et al., 2008). The upstream (promoter) region contains binding sites for the following transcription factors: delta CREB, CREB, NF-kappaB1, NF-kappaB, AP-1, HNF4 alpha2, FOXO1a, MZF-1, Max and c-Myc. Beta-catenin/TCF4 binding and activation of transcription has been experimentally confirmed (Gu et al., 2008).

Transcription

Two protein coding transcripts exist resulting from alternative splicing:
Transcript variant 1 (NM_006546). The length of this transcript is 8769 nt and encompasses all 15 exons (exon 1: 509 bp, exon 2: 60 bp, exon 3: 48 bp, exon 4: 51 bp, exon 5: 63 bp, exon 6: 281 bp, exon 7: 134 bp, exon 8: 122 bp, exon 9: 135 bp, exon 10: 122 bp, exon 11: 119 bp, exon 12: 74 bp, exon 13: 131 bp, exon14: 113 bp, exon 15: 6973 bp).
Several alternative 3 ends (polyadenylation sites) exist at exon 15 3-UTR (marked by flags in the figure above). Translation starts at +335 and ends at +2068.
Transcript variant 2 (NM_001160423.1). It encompasses 8352 bp and lacks two consecutive in-frame exons (6 and 7).
Other spliced variants have been reported without corresponding protein product recorded.

Proteins

Atlas Image
IGF2BP1 protein translated from transcript 1 variant.

Description

The IGF2BP1 protein translated from the transcript variant 1 consists of 577 aa (63,48 kD) and has 2 highly conserved RRM motifs belonging to the RNA recognition motif (RRM) superfamily and 4 KH domains (NP_006537.3). The third and fourth KH domains constitute both the protein dimerization motif and the RNA binding domain. The four KH domains promote granule formation and stress granule targeting (Stöhr et al., 2006). Two nuclear export signals (NES) exist within the second and fourth KH domains (Nielsen et al., 2003). The KH domains have been implicated in the suppression of HIV-1 infectivity (Zhou et al., 2008). Phosphorylation sites are marked (Bennetzen et al., 2010; Dephoure et al., 2008). Phosphorylation of Tyrosine 396 prevents RNA binding and translation inhibition of beta-actin mRNA (Hüttelmaier et al., 2005).
The IGF2BP1 protein translated from transcript 2 variant is predicted to consist of 438 aa (48.597 kD) and contain 2 RRM and 3 KH domains (NP_001153895.1).
Atlas Image
IGF2BP1 protein translated from transcript 2 variant.

Expression

IGF2BP1 is widely expressed in fetal tissues (liver, lung, kidney, thymus, etc), placenta and CD34+ cord blood cells (Nielsen et al., 1999; Ioannidis et al., 2001; Ioannidis et al., 2005). Postnatally it is expressed in ovary (oocytes and granulosa cells), in testis (spermatogonia), in semen (Hammer et al., 2005) and in intestinal crypts (Nielsen et al., 1999; Dimitriadis et al., 2007). It is expressed de novo in kidney, prostate, trachea, testis, ovarian and lung cancer, melanoma, mesenchymal and brain tumors. At protein level, it is expressed in testicular, lung and colon cancer.

Localisation

IGF2BP1 has been detected in the nucleus, cytoplasm, cytoplasmic mRNPs, granules (Nielsen et al., 2002; Nielsen et al., 2003). In stress granules IGF2BP1 co localizes with G3BP1 and TIAL1 (Stöhr et al., 2006). It has also been detected in lamellipodia (Yaniv et al., 2003), growth cones and the leading edge of developing axons (Eom et al., 2003).

Function

mRNA translation: IGF2BP1 regulates translation by binding the 5-UTR of the mRNA of certain genes, including insulin-like growth factor 2 (Nielsen et al., 1999), and beta actin (Hüttelmaier et al., 2005). It has been identified in a HCV IRES-mediated translation complex along with EIF3C and RPS3, enhancing translation of the Hepatitis C virus (HCV) RNA-replicon via the internal ribosome entry site (IRES), without affecting 5cap-dependent translation (Weinlich et al., 2009). IGF2BP1 binds the adenine-rich autoregulatory sequence (ARS) of the 5-UTR of the PABPC1 mRNA in collaboration with CSDE1 and PABPC1 proteins and causes translational repression (Patel and Bag, 2006; Patel et al., 2005).

mRNA stabilization: IGF2BP1 binds to the coding region mRNA stability determinant (CRD) of c-myc mRNA and protects it from endonucleolytic cleavage (Doyle et al.,1998; Lemm and Ross, 2002). It protects MDR-1 mRNAs from endonucleolytic cleavage by binding to a coding region element (Sparanese and Lee, 2007). Also binds to the coding region of betaTrCP1 mRNA and stabilizes it by disrupting miRNA-dependent interaction with AGO2 (Noubissi et al., 2006; Elcheva et al., 2009). Binds and stabilizes GLI1 mRNA causing an elevation of GLI1 expression and transcriptional activity (Noubissi et al., 2009). IGF2BP1 binds to multiple elements in the 3-UTR of the CD44 mRNAs and stabilizes this mRNA (Vikesaa et al., 2006). Binds to the 3-UTR of Micropthalmia associated transcription factor mRNA and prevents the binding of miR-340 to its target sites, resulting in stabilization of the transcript, elevated expression and activity of this transcription factor (Goswami et al., 2010).

mRNA transportation: IGF2BP1 binds to the fourth and fifth exons of the oncofetal H19 RNA (Runge et al., 2000) and with ELAVL4 and G3BP to 3-UTR of the neuron-specific TAU mRNA (Atlas et al., 2004; Atlas et al., 2007) and regulates their localization. In collaboration with IGF2BP2, IGF2BP1 binds to the conserved 54-nucleotide element in the 3-UTR of the beta actin mRNA, known as the zip code. IGF2BP1 promotes the localization of the beta-actin mRNA to dendrites (Eom et al., 2003). IGF2BP1 may act as a regulator of mRNA transport to activated synapses in response to synaptic activity.

Protein binding: IGF2BP1 interacts through the third and fourth KH domains with PABPC1 in a RNA-independent manner (Patel and Bag, 2006) and can form homo- and heterodimers with IGF2BP2 or IGF2BP3 (Nielsen et al., 2004). It interacts with fragile X metal retardation protein isoform 18 (Rackham and Brown, 2004). It interacts with DHX9, ELAVL2, HNRNPA2B1, HNRNPC, HNRNPH1, HNRNPU, IGF2BP2, IGF2BP3, ILF2 and YBX1 (Weindensdorfer et al., 2009). IGF2BP1 was identified in a mRNP granule complex, with hnRNP A1, hnRNP A2/B1, hnRNP D, hnRNP L, hnRNP Q, hnRNP R, hnRNP U, YB1/major core protein, interleukin enhancer-binding factor 2 and 3, PABP1, PABP2, PABP4, nucleolin, RNA helicase A, a series of 40 S ribosomal proteins, and the nuclear cap-binding protein CBP80 (Jønson et al., 2007). IGF2BP1 associates with HIV-1 particles. It interacts (via KH3 and KH4 domains) with HIV-1 GAG protein and diminishes viral RNA packaging, thwarts GAG processing to the cellular membranes, and impedes HIV-1 assembly (Zhou et al., 2008).

Homology

The identity of human IGF2BP1 over an aligned region in UniGene is as follows:
- Pan troglodytes: 99.83%
- Canis lupas familiaris: 90.93%
- Bos taurus: 91.05%
- Mus musculus: 89.43%
- Rattus norvegicus: 89.43%

Implicated in

Entity name
Lung cancer
Disease
IGF2BP1 is expressed in lung cancer and its expression correlates with adverse histological and clinical features and is an indicator of poor prognosis. Suppression of its expression with siRNA suppresses growth of NSCLC cells in vitro (Ioannidis et al., 2004; Kato et al., 2007).
Entity name
Ovarian cancer
Disease
Increased expression of IGF2BP1 mRNA is associated with an advanced clinical stage and poor prognosis in patients with ovarian cancer (Köbel et al., 2007).
Entity name
Testicular cancer
Disease
Detected in testicular carcinomas even in early stage carcinoma in situ (Hammer et al., 2005).
Entity name
Melanoma
Disease
IGF2BP1 is highly expressed in primary human malignant melanomas and melanoma cell line (Elcheva et al., 2008).
Entity name
Breast cancer
Disease
The IGF2BP1 gene is amplified in breast cancer (Doyle et al., 2000). Significant associations are detected between IGF2BP1 expression and the absence of estrogen receptors. IGF2BP1 collaborates with c-myc amplification to render tumours more aggressive (Ioannidis et al., 2003). Tissue specific induced expression in transgenic mice promotes tumor formation (Tessier et al., 2004).
Entity name
Colon cancer
Disease
IGF2BP1 is scarce or absent from normal colon but is over expressed in colorectal cancer. IGF2BP1 positive tumours associate with metastasis/recurrence and shorter survival (Ross et al., 2001; Dimitriadis et al., 2007).
Entity name
Hepatocellular carcinoma
Disease
IGF2BP1 is detected as an autoantigen in hepatocellular carcinoma (Himoto et al., 2005).
Entity name
Oncogenesis
Note
The oncogenic action of IGF2BP1 is effected through the stabilization of the mRNA of oncogenes such as c-myc, betaTrCP1, Gli and upregulation of their expression. IGF2BP1 expression may promote metastasis by shuttling requisite RNAs to the lamellipodia of migrating cells (Vikesaa et al., 2006; Vainer et al., 2008).

Bibliography

Pubmed IDLast YearTitleAuthors
170865422007Dynamic association with polysomes during P19 neuronal differentiation and an untranslated-region-dependent translation regulation of the tau mRNA by the tau mRNA-associated proteins IMP1, HuD, and G3BP1.Atlas R et al
201640592010Site-specific phosphorylation dynamics of the nuclear proteome during the DNA damage response.Bennetzen MV et al
186696482008A quantitative atlas of mitotic phosphorylation.Dephoure N et al
174157132007Expression of oncofetal RNA-binding protein CRD-BP/IMP1 predicts clinical outcome in colon cancer.Dimitriadis E et al
98012971998The c-myc coding region determinant-binding protein: a member of a family of KH domain RNA-binding proteins.Doyle GA et al
108504082000Amplification in human breast cancer of a gene encoding a c-myc mRNA-binding protein.Doyle GA et al
196475202009CRD-BP protects the coding region of betaTrCP1 mRNA from miR-183-mediated degradation.Elcheva I et al
184541742008Overexpression of mRNA-binding protein CRD-BP in malignant melanomas.Elcheva I et al
146141022003Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses.Eom T et al
204394672010MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein.Goswami S et al
184904422008Feedback regulation between zipcode binding protein 1 and beta-catenin mRNAs in breast cancer cells.Gu W et al
160491582005Expression of IGF-II mRNA-binding proteins (IMPs) in gonads and testicular cancer.Hammer NA et al
156451142005Significance of autoantibodies against insulin-like growth factor II mRNA-binding proteins in patients with hepatocellular carcinoma.Himoto T et al
163069942005Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1.Hüttelmaier S et al
157697382005CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells.Ioannidis P et al
172896612007Molecular composition of IMP1 ribonucleoprotein granules.Jønson L et al
172552632007Increased expression of insulin-like growth factor-II messenger RNA-binding protein 1 is associated with tumor progression in patients with lung cancer.Kato T et al
175460462007Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma.Köbel M et al
120240102002Regulation of c-myc mRNA decay by translational pausing in a coding region instability determinant.Lemm I et al
119733502002Cytoplasmic trafficking of IGF-II mRNA-binding protein by conserved KH domains.Nielsen FC et al
129215322003Nuclear transit of human zipcode-binding protein IMP1.Nielsen J et al
98910601999A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development.Nielsen J et al
153142072004Sequential dimerization of human zipcode-binding protein IMP1 on RNA: a cooperative mechanism providing RNP stability.Nielsen J et al
198876152009Wnt signaling stimulates transcriptional outcome of the Hedgehog pathway by stabilizing GLI1 mRNA.Noubissi FK et al
172127832006IMP1 interacts with poly(A)-binding protein (PABP) and the autoregulatory translational control element of PABP-mRNA through the KH III-IV domain.Patel GP et al
163569272005The autoregulatory translational control element of poly(A)-binding protein mRNA forms a heteromeric ribonucleoprotein complex.Patel GP et al
152825482004Visualization of RNA-protein interactions in living cells: FMRP and IMP1 interact on mRNAs.Rackham O et al
116417792001Overexpression of an mRNA-binding protein in human colorectal cancer.Ross J et al
108759292000H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein.Runge S et al
172641152007CRD-BP shields c-myc and MDR-1 RNA from endonucleolytic attack by a mammalian endoribonuclease.Sparanese D et al
171016992006ZBP1 regulates mRNA stability during cellular stress.Stöhr N et al
147296262004Mammary tumor induction in transgenic mice expressing an RNA-binding protein.Tessier CR et al
185359852008A role for VICKZ proteins in the progression of colorectal carcinomas: regulating lamellipodia formation.Vainer G et al
165411072006RNA-binding IMPs promote cell adhesion and invadopodia formation.Vikesaa J et al
190293032009Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs.Weidensdorfer D et al
195417692009IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3'UTR.Weinlich S et al
145228772003The RNA-binding protein Vg1 RBP is required for cell migration during early neural development.Yaniv K et al
183852352008Insulin-like growth factor II mRNA binding protein 1 associates with Gag protein of human immunodeficiency virus type 1, and its overexpression affects virus assembly.Zhou Y et al

Other Information

Locus ID:

NCBI: 10642
MIM: 608288
HGNC: 28866
Ensembl: ENSG00000159217

Variants:

dbSNP: 10642
ClinVar: 10642
TCGA: ENSG00000159217
COSMIC: IGF2BP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000159217ENST00000290341Q9NZI8
ENSG00000159217ENST00000431824Q9NZI8

Expression (GTEx)

0
1
2
3
4
5
6
7
8
9

Pathways

PathwaySourceExternal ID
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Gene ExpressionREACTOMER-HSA-74160
Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs) bind RNAREACTOMER-HSA-428359

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
294761522018Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.144
172896612007Molecular composition of IMP1 ribonucleoprotein granules.92
151218632004Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice.81
196475202009CRD-BP protects the coding region of betaTrCP1 mRNA from miR-183-mediated degradation.77
243975862014Long non-coding RNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-Myc mRNA stability.75
237288522013Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1).73
152825482004Visualization of RNA-protein interactions in living cells: FMRP and IMP1 interact on mRNAs.68
216185192012Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1.54
222790492012IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling.44
119733502002Cytoplasmic trafficking of IGF-II mRNA-binding protein by conserved KH domains.43

Citation

Theoni Trangas ; Panayotis Ioannidis

IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-11-01

Online version: http://atlasgeneticsoncology.org/gene/40969/igf2bp1-(insulin-like-growth-factor-2-mrna-binding-protein-1)