Lemur tail kinase 3 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the LMTK3

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. LMTK3 is often overexpressed in human

cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

where it promotes tumour growth, invasion and metastasis and therapy resistance. It was first identified in 2011 through a kinase screen of regulators of ERα by Giamas et al. who found that it promotes upregulation of ERα through PKC inhibition and inhibits ERα degradation through direct phosphorylation of ERα. Numerous other studies have linked LMTK3 to cancer in

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...

non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

, thyroid malignancies and bladder cancer, among others. A small molecule inhibitor, C28, has now been developed for LMTK3 which shows potent anti-cancer activity ''in vitro'' and ''in vivo''.

Function

The most well-characterised physiological role of LMTK3 is in the central nervous system. LMTK3 is expressed in the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...

and tubercle. LMTK3 knockout mice are more hyperactive and show less signs of anxiety than wild-type counterparts. In addition, the mice showed lower levels of depression-like behaviour in forced swim tests and tail suspension assays. LMTK3 knockout mice also have cognitive impairments and show behaviour related to

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. This may be due to impairment in GluA1 trafficking in neurons. These studies show that LMTK3 plays an important role in the central nervous system.

Clinical significance

LMTK3 is implicated in a number of human cancers as an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

as well as a potential predictive or prognostic biomarker. The most well-known role of LMTK3 is in ERα signalling. In 2011, Giamas et al. showed that LMTK3 is a potent regulator of ERα through a kinome-wide siRNA screen. By examining the effect of depletion of different genes of the expression of an ERα-regulated gene, they showed that LMTK3 knockdown significantly reduces ERα activity. LMTK3 phosphorylates ERα, increasing stability and protecting ERα from

proteasomal degradation Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...

. LMTK3 also inhibits PKC, reducing AKT activity and therefore allowing accumulation of FoxO3 in cells, lifting inhibition of ESR1 transcription, causing an increase in ERα expression. An ''in vivo'' model also showed that LMTK3 siRNA reduces tumour growth in mice injected with MCF7 ER+ cells. Later analyses of clinical data show that LMTK3 is predictive and prognostic in breast cancer. High nuclear and cytoplasmic staining in breast cancer cells for LMTK3 is associated with poor clinical outcomes . LMTK3 is also associated with endocrine resistance in breast cancer. Stebbing et al. showed that LMTK3 regulates a number of genes involved in tamoxifen resistance. LMTK3 overexpression also promotes chemotherapy resistance in breast cancer cells. Later, another study by Giamas' group revealed that LMTK3 is strongly associated with cell invasiveness and metastasis through regulation of integrin subunits. LMTK3 acts through GRB2, inducing RAS activation and CDC42 activation, leading to increased ITGA5 and ITGB1 expression through the transcription factor, serum response factor (SRF). The group also showed that LMTK3 has nuclear roles where is facilitates the interaction between KAP1 (Krüppel-associated box domain-associated protein 1) and a KAP1 phosphatase, PP1α (protein phosphatase 1α). This results in trimethylation of Histone H3 lysine 9 (H3K9me3) at tumour suppressor-like genes, resulting in silencing and a downregulation of tumour suppressors in breast cancer. Giamas' group discovered the small molecule inhibitor, C28 in 2020 which is a potent, selective inhibitor of LMTK3. C28 is an orally available and highly selective ATP-competitive inhibitor of LMTK3. Data from the NCI-60 cell line panel and experiments in xenografts show that the drug is an effective inhibitor of breast cancer growth ''in vivo''. LMTK3 is an HSP90-CDC37 client protein which requires this interaction for folding and stability. C28 is a competitive inhibitor of LMTK3 that also deprives LMTK3 of HSP90, promoting instability and degradation of LMTK3. More recently, another compound, C36 has been characterised as a selective inhibitor of LMTK3 with apoptosis-promoting properties in breast cancer cells.

References

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