Mini-reviewEmerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression
Introduction
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an evolutionarily conserved factor encoded by a gene that has been mapped to chromosome 9 in humans [1]. It belongs to the large family of proteins which bind to nascent RNA polymerase II transcripts and are called heterogeneous nuclear RNAs to describe their cellular localization and heterogeneous sizes [2]. HnRNP K was first discovered, more than 25 years ago, as a component of hnRNP particles by two dimensional gel of the immunopurified complex [3]. About 20 major proteins were resolved and designed A1 to U. These proteins showed distinct RNA-binding specificity. With respect to the other hnRNPs, hnRNP K bound preferentially and tenaciously to poly(C) [4] and did not contain RNA-binding consensus sequence but three repeats of a motif termed KH domain (for K homology) [5].
KH domains consist of approximately 65–70 amino acids (aa) highly conserved from bacteria to mammals, whose relevant function is RNA or single-stranded DNA recognition [5]. Four other proteins, αCP-1 (or hnRNP E1), αCP-2 (or hnRNP E2), αCP-3 and αCP-4 are structurally related to hnRNP K. All these proteins, definite poly(C)-binding proteins (PCBPs), contain two consecutive KH domains positioned near the N-terminus and a third located at the carboxyl terminus. Each KH domain consists of a β-sheet composed of three antiparallel β-strands abutted by three α-helics; two unstructured surface loops extend from this structure. These loops are responsible of nucleic acid binding specificity [6].
In addition, hnRNP K contains a nuclear-localization signal (NLS) that mediates its transport from the cytoplasm to the nucleus [7] and a nuclear shuttling domain (KNS) that confers the ability to translocate bi-directionally through the nuclear pore complex [8]. Positioned between the KH2 and KH3 domains is an unstructured region called K-protein-interactive (KI) that is responsible for most of the known interactions between hnRNP K and other proteins [9]. Overall, this modular structure is accountable for multiple interactions between hnRNP K and several of its molecular partners (DNA, RNA and proteins) (Fig. 1A).
Four alternatively spliced isoforms of hnRNP K are known. Isoform 1 differs from isoform 2 due to a few aa in the C-terminus (isoform 1 459SGKFF463, isoform 2 459ADVEGF464). Isoform 3 and isoform 4 correspond to isoform 1 and isoform 2, respectively, without aa 111–134 [10], [11] (Fig. 1A and B). The predicted molecular weight of hnRNP K is within the range of 48–51 kDa. However, in conventional SDS–PAGE, it migrates in a single band of 66 kDa when the protein is localized in the cytoplasm and in double bands of 66 and 64 kDa when it is present in the nucleus. This property indicates that isoforms 3 and 4 are absent from the cytoplasmic fraction.
Section snippets
HnRNP K post-translational modifications
HnRNP K is subject to several post-translational modifications, such as methylation, sumoylation and phosphorylation, which can regulate its interactions with different molecules and influence its functions. In the hnRNP K amino acid sequence, five major (Arg256, Arg258, Arg268, Arg296 and Arg299) and two minor (Arg287 and Arg303) arginines are asymmetrically dimethylated by protein-arginine methyl-transferase I [12], [13], the only enzyme methylating the protein both in vitro and in vivo [14].
Molecular functions of hnRNP K
HnRNP K has been found to be associated with actively proliferating cells [25], [26], and it is involved in all the mechanisms implicated in gene regulation through a plethora of DNA, RNA and protein interactions due, as reported above, to its particular structure that may serve as a docking platform for the assembly of multimolecular signaling complexes, facilitating cross-talk between kinases and factors that mediate nucleic acid-directed processes [20] (Fig. 1C). Here, we will briefly
The role of hnRNP K in cancer cells
Both the many cellular functions discussed above and the interactions with oncogenes, tumor suppressor genes and noncoding RNAs point to an involvement of hnRNP K in malignant cell transformation.
Conclusions and perspectives
The results here reported collectively suggest that tumor cells are characterized by increased levels of hnRNP K and by a modification of the phosphorylation status of the protein. Abnormal activation of the Ras/Raf/MEK/ERK pathway occurs in human cancer [100] and, as reported above, it is known that ERK phosphorylates hnRNP K in the nucleus, after which the phosphorylated protein translocates to the cytoplasm and inhibits mRNA translation [22]. Moreover, ERK-phospho acceptor-sites mutant in
Conflict of interest
The authors declare that they have no conflict of interest
Acknowledgement
This study was partially supported by grants from Compagnia di San Paolo (Grant No. 2012.1588) and Project 5x1000 IRCCS AOU San Martino-IST
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2022, American Journal of Human GeneticsCitation Excerpt :This approach is particularly helpful in rare disorders where there have been only a limited number of reported individuals and when there are missense variants, splice variants, or non-coding variants, which are more difficult to interpret. HNRNPK encodes the heterogeneous nuclear ribonucleoprotein K (hnRNP K), a conserved and ubiquitously expressed nucleic-acid-binding protein involved in many gene expression processes, including chromatin remodeling, transcription, RNA stability, splicing, translation, post-translational modification, and signal transduction (reviewed in Barboro et al.18). It has been implicated in the regulation of both tumor-suppressive and oncogenic pathways.
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2022, Experimental HematologyCitation Excerpt :When hnRNPK was knocked down, imatinib sensitivity was partially restored in SUP/B15-IM cells, suggesting that the overexpression of this RNA-binding protein may play a role in the development of TKI resistance in Ph+ ALL cells. Previous studies have elegantly demonstrated that hnRNPK can serve as a docking protein that can integrate multiple signaling pathways and nucleic acid-directed processes [16], and there is strong evidence that hnRNPK is an important mediator of oncogenesis owing to its ability to regulate activities including transcription, splicing, and translation [17]. Chen et al. [18], for example, found hnRNPK to be linked to poor bladder cancer prognosis owing to its ability to regulate the balance between cellular proliferation and apoptosis.