Interaction of two translational components, lysyl‐tRNA synthetase and p40/37LRP, in plasma membrane promotes laminin‐dependent cell migration

Kwon

Topics in Current Chemistry

2013

Self Cite

Although aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) have long been recognized as housekeeping proteins, evidence indicating that they play a key role in regulating cancer is now accumulating. In this chapter we will review the conventional and non-conventional functions of ARSs and AIMPs with respect to carcinogenesis. First, we will address how ARSs and AIMPs are altered in terms of expression, mutation, splicing, and post-translational modifications. Second, the molecular mechanisms for ARSs' and AIMPs' involvement in the initiation, maintenance, and progress of carcinogenesis will be covered. Finally, we will introduce the development of therapeutic approaches that target ARSs and AIMPs with the goal of treating cancer.

Section: Aminoacyl-trna Synthetasesmentioning

confidence: 91%

“…Glutaminyl-tRNA synthetase (QRS) also sustains proliferative signaling in the presence of glutamine [23]. KRS promotes cancer cell migration [24] and glutamyl-proryl-tRNA synthetase (EPRS), seryl-tRNA synthetase (SRS), TRS, WRS, and YRS are considered as angiogenesis-regulating factors [5,14,15,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Association of Aminoacyl-tRNA Synthetases with Cancer

Kwon

Topics in Current Chemistry

2013

Self Cite

“…A high-throughput two-hybrid study predicted that C6orf106 could combine with ribosomal protein SA (RPSA) [2]. RPSA was highly expressed in the colon cancer, breast cancer, ovarian cancer, and other malignant cancers [3][4][5][6], and significantly associated with the proliferation, invasion, and metastasis of tumor [7][8][9][10][11][12][13][14]. Since it could interact with RPSA, C6orf106 might also be related with the proliferation, invasion, and metastasis of the tumors.…”

Section: Introductionmentioning

confidence: 99%

A novel biomarker C6orf106 promotes the malignant progression of breast cancer

Jiang

Zhang

et al. 2015

Tumor Biol.

C6orf106 (chromosome 6 open reading frame 106) is a recently discovered protein encoded by the 6th chromosome. Though many proteins encoded by chromosome 6 are reportedly related to cancer, schizophrenia, autoimmunity and many other diseases, the function of C6orf106 was not well demonstrated so far. As measured by immunohistochemical staining, C6orf106 was positive in normal breast duct myoepithelial cells (92.31 %, 72/78), but negative in normal breast duct glandular epithelial cells (3.85 %, 3/78). In breast ductal carcinoma in situ, C6orf106 showed weakly or moderately positive (77.97 %, 46/59), but it was significantly strongly positive in invasive ductal carcinoma (79.57 %, 148/186). The expression intensity of C6orf106 seemed increased significantly along with the malignancy of breast cancer (p < 0.001). Additionally, C6orf106 expression was significantly correlated with TNM stage (p = 0.001 and p = 0.004) and lymph node metastasis (p = 0.018 and p = 0.025) of the overall and the triple-negative breast cancer, respectively. Consistently, we found that the interference of C6orf106 was able to inhibit cell proliferation and invasion of two triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, accompanied by the decrease of cyclin A2, cyclin B1, c-myc, and N-cadherin and the increase of E-cadherin. Collectively, these results indicate that C6orf106 may promote tumor progression in the invasive breast cancer, particularly in triple-negative breast cancer, and C6orf106 might serve as a novel therapeutic target of breast cancer, especially for triple-negative breast cancer.

“…LysRS is then released from the MSC and traffics to the nucleus (18,19), where it synthesizes a dinucleotide Ap4A, triggering transcriptional activation of several genes (20)(21)(22). In another example, following laminin receptor (67LR) stimulation of a variety of human cell lines, LysRS is phosphorylated on residue T52 by mitogen-activated protein kinase (MAPK), released from the MSC, and trafficked to the plasma membrane, where it interacts with 67LR, protecting it from ubiquitin-mediated degradation (23). LysRS can also be released from the MSC and secreted to act as a proinflammatory cytokine (24).…”

mentioning

confidence: 99%

HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

Duchon

Gelais

Titkemeier

et al. 2017

J Virol

A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNA Lys3 to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyltRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNA Lys3 localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication.IMPORTANCE Human tRNA Lys3 , the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNA Lys3 packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNA Lys3 and LysRS packaging remain unknown. LysRS is normally sequestered in a high-molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNA Lys . Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1-producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function.KEYWORDS lysyl-tRNA synthetase, human immunodeficiency virus, multisynthetase complex, nuclear localization, tRNA primer packaging