KARS

Official Full Name

KRAS proto-oncogene, GTPase

Organism

Homo sapiens

GeneID

3845

Background

This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

Synonyms

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras2;

Protein Sequence

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM

Open

Disease

Pancreatic cancer

Approved Drug

2 +

Clinical Trial Drug

9 +

Discontinued Drug

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Detailed Information

KARS (Lysyl-tRNA synthetase) is classified as a protein-coding gene. Among the many disorders, it is linked to include Autosomal Recessive Deafness 89, Recessive Intermediate B, and Charcot-Marie-Tooth disease. Emphasizing its vital function in the larger framework of protein synthesis, KARS engages in several biological processes like tRNA aminoacylation and peptide chain elongation. KARS also has a significant paralog, DARS2, which suggests the evolutionary preservation of this gene family.

Functionality of KARS

By means of a two-step process, KARS catalyzes the particular lysine attachment to its cognate tRNA. Adenosine triphosphate (ATP) first activates lysine to generate aminoacyl-adenylate (AA-AMP), which then passes to the acceptor end of the tRNA. The precision of translation depends on the proper amino acid being connected to the suitable tRNA, so this step is crucial for guaranteeing the fidelity of protein synthesis.

Furthermore, when released, KARS is known to function as a signaling protein that triggers monocytes/macrophages to initiate immunological reactions. This dual activity as both a signaling molecule and a metabolic enzyme emphasizes KARS' multifarious character. KARS also accelerates the manufacture of diadenosine tetraphosphate (Ap4A), a chemical known to disturb the interaction between HINT1 and MITF, hence triggering MITF transcriptional activity. This feature of KARS activity suggests its participation in intricate regulatory systems going beyond basic protein synthesis.

KARS also interacts with viral proteins, including the HIV-1 GAG protein, therefore enabling the selective packaging of tRNA(Lys), a primer for reverse transcription initiation. This interaction emphasizes KARS's importance in viral life cycles as well as in cellular metabolism, therefore stressing its part in the pathogenesis of viral diseases.

Normal KARS Protein Pathway

Receptor monomers on the cell membrane—epidermal growth factor receptor (EGFR), HER2, ErbB3, and ErbB4—dimerize upon interaction with external ligands in normal cells. Autophosphorylation and then phosphorylation of downstream signaling proteins follow from this dimerization. Grb2-Shc is one important signaling route turned on during this process; it then activates the guanine nucleotide exchange factor, SOS. The KARS protein cannot be activated without the SOS protein.

Figure 1 illustrates the RAS signaling pathways in mammalian cells, highlighting how active RAS regulates key pathways involved in cell cycle progression, migration, and tumorigenesis, as well as the implications of oncogenic mutations and farnesyltransferase inhibitors on RAS function. Figure 1. RAS Signaling Pathways in Mammalian Cells. (Berndt N, et al., 2011)

KARS is strongly linked to guanosine diphosphate (GDP) in its inactive form. SOS causes KARS to switch GDP for guanosine triphosphate (GTP). GTP binds to KARS and endows it with guanine nucleotide exchange activity, therefore activating downstream signaling pathways. Among these pathways include the activation of many downstream proteins including PLC-ε, RALGDS, TIAM1, RIN1, phosphoinositide 3-kinase (PI3K), and Raf protein family.

Later on, the activation of these downstream signaling proteins starts other signaling cascades that propel important cellular activities like migration and cell multiplication. This complex network of signals emphasizes the crucial function of KARS in proper cellular functioning.

Mutations in KARS

Mostly occurring at either the 12th or 13th amino acid position, mutations in the KARS gene are somewhat common. Of them, G13D, G12D, and G12V are the most often occurring mutations. KARS maintains a constant connection with GTP when it undergoes these mutations, which produces an active state always. This continuous activation therefore results in the continuous stimulation of downstream signaling pathways, which fuels too high cell proliferation and migration.

Several cancer types show very high KARS mutations according to statistical studies. For example, KARS mutations abound in around 61% of pancreatic malignancies, 43% of colorectal cancers, 21% of endometrial cancers, and 26% of lung adenocarcinomas. This great frequency emphasizes the important part KARS mutations play in the oncogenic mechanisms causing various cancers.

Targeted treatments aimed at EGFR, including cetuximab and erlotinib, frequently provide poor therapeutic responses for individuals with tumors carrying activating KARS mutations. Moreover, these individuals usually have worse prognosis; survival rates are much lower than those of patients without KARS mutations. Consequently, determining the success of EGFR inhibitor treatments now depends critically on the identification of activating KARS mutations. KARS mutation testing has therefore become a necessary companion diagnostic tool for focused cancer treatments as it helps to integrate many aspects.

References:

Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011;11(11):775-791.
Young HJ, Lee JW, Kim S. Function of membranous lysyl-tRNA synthetase and its implication for tumorigenesis. Biochim Biophys Acta. 2016;1864(12):1707-1713.
Ofir-Birin Y, Fang P, Bennett SP, et al. Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol Cell. 2013;49(1):30-42.

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