O42254 (IF2B1_CHICK) Reviewed, UniProtKB/Swiss-Prot
Last modified May 14, 2014. Version 93. History...
Names and origin
|Protein names||Recommended name:|
Insulin-like growth factor 2 mRNA-binding protein 1
Short name=IGF2 mRNA-binding protein 1
IGF-II mRNA-binding protein 1
VICKZ family member 1
Zip-code binding polypeptide
Zipcode-binding protein 1
|Organism||Gallus gallus (Chicken) [Reference proteome]|
|Taxonomic identifier||9031 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Testudines + Archosauria group › Archosauria › Dinosauria › Saurischia › Theropoda › Coelurosauria › Aves › Neognathae › Galliformes › Phasianidae › Phasianinae › Gallus|
|Sequence length||576 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation. Plays a direct role in the transport and translation of transcripts required for axonal regeneration in adult sensory neurons By similarity. Regulates localized beta-actin/ACTB mRNA translation in polarized cells, a crucial process for cell migration and neurite outgrowth. Co-transcriptionally associates with the ACTB mRNA in the nucleus. This binding involves by a conserved 54-nucleotide element in the ACTB mRNA 3'-UTR, known as the 'zipcode'. The ribonucleoparticle (RNP) thus formed is exported to the cytoplasm, binds to a motor protein and is transported along the cytoskeleton to the cell periphery. During transport, IGF2BP1 prevents beta-actin mRNA from being translated into protein. When the RNP complex reaches its destination near the plasma membrane, IGF2BP1 is phosphorylated by SRC. This releases the mRNA, allowing ribosomal 40S and 60S subunits to assemble and initiate ACTB protein synthesis. The monomeric ACTB protein then assembles into the subcortical actin cytoskeleton, which pushes the leading edge onwards. Binds MYC mRNA. Promotes the directed movement of cells by fine-tuning intracellular signaling networks. Binds to MAPK4 3'-UTR and inhibits its translation. Interacts with PTEN transcript open reading frame (ORF) and prevents mRNA decay. This combined action on MAPK4 (down-regulation) and PTEN (up-regulation) antagonizes HSPB1 phosphorylation, consequently it prevents G-actin sequestration by phosphorylated HSPB1, allowing F-actin polymerization. Hence enhances the velocity of cell migration and stimulates directed cell migration by PTEN-modulated polarization. Ref.1 Ref.2 Ref.3 Ref.4 Ref.6 Ref.7 Ref.8
Can form homooligomers and heterooligomers with IGF2BP1 and IGF2BP3 in an RNA-dependent manner. Associates with the cytoskeleton, predominantly with actin filament bundles and occasionnally with microtubules. In a heterologous system, interacts with ELAVL1, DHX9 and HNRNPU. Ref.8
Nucleus. Cytoplasm. Cytoplasm › perinuclear region. Cell projection › growth cone. Cell projection › filopodium. Cell projection › lamellipodium. Note: In the nucleus, located in discrete foci, coinciding with the sites of ACTB transcription. Export from the nucleus is mediated by XPO1. In the cytoplasm, colocalizes with ACTB mRNA at the leading edge, in growth cone filopodia and along neurites. In these locations, also colocalizes with microtubules. Colocalization with ACTB mRNA is partially lost at the cell periphery, suggesting release of the transcript. In neuronal processes, exhibits fast retrograde and anterograde movements, when associated with ACTB mRNA; this motility is lost when the association is inhibited. In migrating fibroblasts, localizes not only to leading edges, but also to retracting tails. In response to cellular stress, such as oxidative stress or heat shock, recruited to stress granules. Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.8
Domain KH3 and KH4 are the major RNA-binding modules, although KH1 and KH2 may also contribute to transcript binding. The contribution to RNA-binding of individual KH domains may be target-specific. KH1 and KH2, and possibly KH3 and KH4, promote the formation of higher ordered protein-RNA complexes, which may be essential for IGF2BP1 cytoplasmic retention. KH domains are required for RNA-dependent homo- and heterooligomerization and for localization to stress granules. KH3 and KH4 mediate association with the cytoskeleton. Two nuclear export signals (NES) have been identified in KH2 and KH4 domains, respectively. Only KH2 NES is XPO1-dependent. Both NES may be redundant, since individual in vitro mutations do not affect subcellular location of the full length protein By similarity. Ref.4 Ref.8
Phosphorylated by SRC at Tyr-396. This residue is involved in ACTB mRNA binding, its phosphorylation impairs association with ACTB mRNA and hence abolishes translational repression. Phosphorylation occurs in close proximity to filopodia and in the growth cones of differentiated neuroglioblastoma cells. Ref.6
Belongs to the RRM IMP/VICKZ family.
Contains 4 KH domains.
Contains 2 RRM (RNA recognition motif) domains.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 576||576||Insulin-like growth factor 2 mRNA-binding protein 1||PRO_0000282536|
|Domain||2 – 75||74||RRM 1|
|Domain||81 – 156||76||RRM 2|
|Domain||195 – 260||66||KH 1|
|Domain||276 – 343||68||KH 2|
|Domain||404 – 469||66||KH 3|
|Domain||486 – 552||67||KH 4|
Amino acid modifications
|Modified residue||396||1||Phosphotyrosine; by SRC Ref.6|
|Mutagenesis||213||1||K → E: Decrease in Y RNA binding. Only small decrease in affinity for binding to ACTB and MYC transcripts, some accumulation in the nucleus, and complete loss of formation of higher ordered protein-RNA complexes; when associated with E-294. Loss of homo- and heterooligomerization with IGF2BP1 and IGF2BP2, almost complete loss of ACTB and MYC transcript binding, almost complete loss of ELAVL1-, DHX9- and HNRNPU-binding and perturbed subcellular location, including accumulation in the nucleus and loss of localization to stress granules; when associated with E-294, 422-E-E-423 and 505-E-E-506. Ref.8|
|Mutagenesis||294||1||K → E: Decrease in Y RNA binding. Only small decrease in affinity for binding to ACTB and MYC transcripts, some accumulation in the nucleus, and complete loss of formation of higher ordered protein-RNA complexes; when associated with E-213. Loss of homo- and heterooligomerization with IGF2BP1 and IGF2BP2, almost complete loss of ACTB and MYC transcript binding, almost complete loss of ELAVL1-, DHX9- and HNRNPU-binding and accumulation in the nucleus; when associated with E-213, 422-E-E-423 and 505-E-E-506. Ref.8|
|Mutagenesis||396||1||Y → F: Increases the interaction with ACTB mRNA and its translational repression. Ref.6|
|Mutagenesis||396||1||Y → Q: Impairs the interaction with beta-actin mRNA and its translation repression. Ref.6|
|Mutagenesis||422 – 423||2||KK → EE: Almost complete loss of Y RNA binding. About 80-fold decrease in affinity for binding to ACTB transcript, but almost no effect on MYC transcript binding; when associated with 505-E-E-506. Loss of homo- and heterooligomerization with IGF2BP1 and IGF2BP2, almost complete loss of ACTB and MYC transcript binding, almost complete loss of ELAVL1-, DHX9- and HNRNPU-binding and accumulation in the nucleus; when associated with E-213, E-294 and 505-E-E-506.|
|Mutagenesis||504 – 505||2||KG → EE: Decrease in Y RNA binding. About 80-fold decrease in affinity for binding to ACTB transcript, but almost no effect on MYC transcript binding; when associated with 422-E-E-423. Loss of homo- and heterooligomerization with IGF2BP1 and IGF2BP2, almost complete loss of ACTB and MYC transcript binding, almost complete loss of ELAVL1-, DHX9- and HNRNPU-binding and accumulation in the nucleus; when associated with E-213, E-294 and 422-E-E-423.|
|||"Characterization of a beta-actin mRNA zipcode-binding protein."|
Ross A.F., Oleynikov Y., Kislauskis E.H., Taneja K.L., Singer R.H.
Mol. Cell. Biol. 17:2158-2165(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, RNA-BINDING, TISSUE SPECIFICITY.
Tissue: Embryonic fibroblast.
|||"Neurotrophin-induced transport of a beta-actin mRNP complex increases beta-actin levels and stimulates growth cone motility."|
Zhang H.L., Eom T., Oleynikov Y., Shenoy S.M., Liebelt D.A., Dictenberg J.B., Singer R.H., Bassell G.J.
Neuron 31:261-275(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
|||"Real-time visualization of ZBP1 association with beta-actin mRNA during transcription and localization."|
Oleynikov Y., Singer R.H.
Curr. Biol. 13:199-207(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, RNA-BINDING, ASSOCIATION WITH CYTOSKELETON, SUBCELLULAR LOCATION.
|||"Two ZBP1 KH domains facilitate beta-actin mRNA localization, granule formation, and cytoskeletal attachment."|
Farina K.L., Huttelmaier S., Musunuru K., Darnell R., Singer R.H.
J. Cell Biol. 160:77-87(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, RNA-BINDING, ASSOCIATION WITH CYTOSKELETON, SUBCELLULAR LOCATION, DOMAIN.
|||"ZBP1 regulates mRNA stability during cellular stress."|
Stoehr N., Lederer M., Reinke C., Meyer S., Hatzfeld M., Singer R.H., Huettelmaier S.
J. Cell Biol. 175:527-534(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
|||"Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1."|
Huttelmaier S., Zenklusen D., Lederer M., Dictenberg J., Lorenz M., Meng X., Bassell G.J., Condeelis J., Singer R.H.
Nature 438:512-515(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT TYR-396, MUTAGENESIS OF TYR-396, SUBCELLULAR LOCATION.
|||"IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling."|
Stohr N., Kohn M., Lederer M., Glass M., Reinke C., Singer R.H., Huttelmaier S.
Genes Dev. 26:176-189(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION.
|||"Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains."|
Wachter K., Kohn M., Stohr N., Huttelmaier S.
Biol. Chem. 394:1077-1090(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, RNA-BINDING, OLIGOMERIZATION, INTERACTION WITH ELAVL1; DHX9 AND HNRNPU, SUBCELLULAR LOCATION, DOMAIN, MUTAGENESIS OF LYS-213; LYS-294; 423-LYS-LYS-424 AND 505-LYS-GLY-506.
|||"Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression?"|
Bell J.L., Wachter K., Muhleck B., Pazaitis N., Kohn M., Lederer M., Huttelmaier S.
Cell. Mol. Life Sci. 70:2657-2675(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|AF026527 mRNA. Translation: AAB82295.1.|
|RefSeq||NP_990402.1. NM_205071.1. |
3D structure databases
|SMR||O42254. Positions 1-161. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSGALT00000001975; ENSGALP00000001973; ENSGALG00000001293. |
Family and domain databases
|Gene3D||3.30.1370.10. 4 hits. |
188.8.131.520. 2 hits.
|InterPro||IPR004087. KH_dom. |
|Pfam||PF00013. KH_1. 4 hits. |
PF00076. RRM_1. 1 hit.
|SMART||SM00322. KH. 4 hits. |
SM00360. RRM. 2 hits.
|SUPFAM||SSF54791. SSF54791. 4 hits. |
|PROSITE||PS50084. KH_TYPE_1. 4 hits. |
PS50102. RRM. 2 hits.
|Accession||Primary (citable) accession number: O42254|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families