Cancer Letters

Cancer Letters

Volume 352, Issue 2, 1 October 2014, Pages 152-159
Cancer Letters

Mini-review
Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression

https://doi.org/10.1016/j.canlet.2014.06.019Get rights and content

Highlights

  • hnRNP K acts as a docking platform to facilitate molecular interactions.

  • hnRNP K is involved in transcriptional processes as an activator or a repressor.

  • hnRNP K and ncRNAs interact to control the expression of target genes.

  • Tumor cells are characterized by increased levels of hnRNP K.

  • hnRNP K aberrant cytoplasmic localization is associated with a worse prognosis.

Abstract

The heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a nucleic acid-binding protein that serves as a docking platform integrating transduction pathways to nucleic acid -directed processes. Recently, this protein has emerged as an important player in carcinogenesis process. HnRNP K is overexpressed in several human cancers and its aberrant cytoplasmic localization has been associated with a worse prognosis for patients, suggesting that it has a role in cancer progression. Herein, we provide a brief overview of the multifunctional roles of hnRNP K and discuss clinical studies that have demonstrated its involvement in cancer development and 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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