HNRNPK

Heterogeneous nuclear ribonucleoprotein K (also protein K) is a protein that in humans is encoded by the HNRNPK gene.[5] It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein particles. The simian homolog is known as protein H16. Both proteins bind to single-stranded DNA as well as to RNA and can stimulate the activity of RNA polymerase II, the protein responsible for most gene transcription. The relative affinities of the proteins for DNA and RNA vary with solution conditions and are inversely correlated, so that conditions promoting strong DNA binding result in weak RNA binding.[6]

HNRNPK
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHNRNPK, CSBP, HNRPK, TUNP, AUKS, heterogeneous nuclear ribonucleoprotein K
External IDsOMIM: 600712 MGI: 99894 HomoloGene: 81909 GeneCards: HNRNPK
Orthologs
SpeciesHumanMouse
Entrez

3190

15387

Ensembl

ENSG00000165119

ENSMUSG00000021546

UniProt

P61978

P61979

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 9: 83.97 – 83.98 MbChr 13: 58.39 – 58.4 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

RNA binding protein domains in other proteins that are similar to the RNA binding domain of protein K are called K-homology or KH domains.

Protein K has been the subject of study related to colorectal cancer, in which an RNA editing event inducing the expression of an isoform containing a point mutation was found to be specific to cancerous cells.[7]

Function

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins, and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm.

The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene is located in the nucleoplasm and has three repeats of KH domains that binds to RNAs. It is distinct among other hnRNP proteins in its binding preference; it binds tenaciously to poly(C). This protein is also thought to have a role during cell cycle progression. Multiple alternatively spliced transcript variants have been described for this gene, but only three variants have been fully described.[8]

Mutations in both copies of HNRNPK are embryonic lethal in mice. Mice with both copies of the gene knocked out die before the 14th day of embryonic development.[9]

Clinical significance

Okamoto syndrome

Mutations in HNRNPK cause Okamoto syndrome, also known as Au–Kline syndrome.[10]

Blood cancers

Deletions in the region encompassing HNRNPK have been found in the cells of acute myeloid leukemia in approximately 2% of cases. Additionally, a majority of mice who have had one of their HNRNPK genes artificially knocked out developed myeloid cancers, with a third developing lymphoid cancers and 4% developing hepatocellular carcinomas. The mice were also smaller, had less developed organs and had higher postnatal mortality (30%). The median lifespan of the mice that survived was less than 50% that of wild-type mice. Deficiencies in HNRNPK appear to specifically reduce the levels of the p42 isoform of CEBPA, which is a transcription factor involved in the differentiation of certain blood cells, as well as p21 (cyclin-dependent kinase inhibitor 1), which is involved in pausing cell development for DNA repair.[11]

HNRNPK overexpression also appears to contribute to cancers via a different mechanism involving translation rather than transcription.[11]

Interactions

HNRPK has been shown to interact with:

Human proteins containing a KH domain

AKAP1; ANKHD1; ANKRD17; ASCC1; BICC1; DDX43; DDX53; DPPA5; FMR1; FUBP1; FUBP3; FXR1; FXR2; HDLBP; HNRPK; IGF2BP1; IGF2BP2; IGF2BP3; KHDRBS1; KHDRBS2; KHDRBS3; KHSRP; KRR1; MEX3A; MEX3B; MEX3C; MEX3D; NOVA1; NOVA2; PCBP1; PCBP2; PCBP3; PCBP4; PNO1; PNPT1; QKI; SF1; TDRKH;

References
  1. GRCh38: Ensembl release 89: ENSG00000165119 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000021546 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Dejgaard K, Leffers H, Rasmussen HH, Madsen P, Kruse TA, Gesser B, et al. (February 1994). "Identification, molecular cloning, expression and chromosome mapping of a family of transformation upregulated hnRNP-K proteins derived by alternative splicing". Journal of Molecular Biology. 236 (1): 33–48. doi:10.1006/jmbi.1994.1116. PMID 8107114.
  6. Gaillard C, Cabannes E, Strauss F (October 1994). "Identity of the RNA-binding protein K of hnRNP particles with protein H16, a sequence-specific single strand DNA-binding protein". Nucleic Acids Research. 22 (20): 4183–6. doi:10.1093/nar/22.20.4183. PMC 331915. PMID 7524036.
  7. Klimek-Tomczak K, Mikula M, Dzwonek A, Paziewska A, Karczmarski J, Hennig E, et al. (February 2006). "Editing of hnRNP K protein mRNA in colorectal adenocarcinoma and surrounding mucosa". British Journal of Cancer. 94 (4): 586–92. doi:10.1038/sj.bjc.6602938. PMC 2361188. PMID 16404425.
  8. "Entrez Gene: HNRPK heterogeneous nuclear ribonucleoprotein K".
  9. Gallardo M, Lee HJ, Zhang X, Bueso-Ramos C, Pageon LR, McArthur M, et al. (October 2015). "hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies". Cancer Cell. 28 (4): 486–499. doi:10.1016/j.ccell.2015.09.001. PMC 4652598. PMID 26412324.
  10. Reference, Genetics Home. "Au-Kline syndrome". Genetics Home Reference. Retrieved 2019-11-30.
  11. Gallardo M, Lee HJ, Zhang X, Bueso-Ramos C, Pageon LR, McArthur M, et al. (October 2015). "hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies". Cancer Cell. 28 (4): 486–499. doi:10.1016/j.ccell.2015.09.001. PMC 4652598. PMID 26412324.
  12. Ostareck-Lederer A, Ostareck DH, Cans C, Neubauer G, Bomsztyk K, Superti-Furga G, Hentze MW (July 2002). "c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs". Molecular and Cellular Biology. 22 (13): 4535–43. doi:10.1128/mcb.22.13.4535-4543.2002. PMC 133888. PMID 12052863.
  13. Chen HC, Lin WC, Tsay YG, Lee SC, Chang CJ (October 2002). "An RNA helicase, DDX1, interacting with poly(A) RNA and heterogeneous nuclear ribonucleoprotein K". The Journal of Biological Chemistry. 277 (43): 40403–9. doi:10.1074/jbc.M206981200. PMID 12183465.
  14. Kim JH, Hahm B, Kim YK, Choi M, Jang SK (May 2000). "Protein-protein interaction among hnRNPs shuttling between nucleus and cytoplasm". Journal of Molecular Biology. 298 (3): 395–405. doi:10.1006/jmbi.2000.3687. PMID 10772858.
  15. Yang JP, Reddy TR, Truong KT, Suhasini M, Wong-Staal F (October 2002). "Functional interaction of Sam68 and heterogeneous nuclear ribonucleoprotein K". Oncogene. 21 (47): 7187–94. doi:10.1038/sj.onc.1205759. PMID 12370808.
  16. Côté J, Boisvert FM, Boulanger MC, Bedford MT, Richard S (January 2003). "Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1". Molecular Biology of the Cell. 14 (1): 274–87. doi:10.1091/mbc.E02-08-0484. PMC 140244. PMID 12529443.
  17. Wada K, Inoue K, Hagiwara M (August 2002). "Identification of methylated proteins by protein arginine N-methyltransferase 1, PRMT1, with a new expression cloning strategy". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1591 (1–3): 1–10. doi:10.1016/s0167-4889(02)00202-1. PMID 12183049.

Further reading
  • Overview of all the structural information available in the PDB for UniProt: P61978 (Human Heterogeneous nuclear ribonucleoprotein K (HNRPK)) at the PDBe-KB.
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