LMTK3 explained

Lemur tail kinase 3 is a protein that in humans is encoded by the LMTK3 gene.[1] [2]

LMTK3 is often overexpressed in human cancers 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.[3] 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,[4] non-small cell lung cancer,[5] thyroid malignancies[6] and bladder cancer,[7] 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, striatum, cerebellum, hippocampus, olfactory bulb and tubercle.[8] 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.[9] LMTK3 knockout mice also have cognitive impairments and show behaviour related to schizophrenia and bipolar disorder. This may be due to impairment in GluA1 trafficking in neurons.[10] 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 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. 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 .[11]

LMTK3 is also associated with endocrine resistance in breast cancer.[12] 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.[13]

Later, another study by Giamas' group revealed that LMTK3 is strongly associated with cell invasiveness and metastasis through regulation of integrin subunits.[14] 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).[15] 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.[16] 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.[17]

Notes and References

  1. Ditsiou A, Gagliano T, Samuels M, Vella V, Tolias C, Giamas G . The multifaceted role of lemur tyrosine kinase 3 in health and disease . Open Biology . 11 . 9 . 210218 . September 2021 . 34582708 . 8478525 . 10.1098/rsob.210218 .
  2. Wendler F, Purice TM, Simon T, Stebbing J, Giamas G . The LMTK-family of kinases: Emerging important players in cell physiology and pathogenesis . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1867 . 9 . 165372 . September 2021 . 30597196 . 10.1016/j.bbadis.2018.12.023 .
  3. Giamas G, Filipović A, Jacob J, Messier W, Zhang H, Yang D, Zhang W, Shifa BA, Photiou A, Tralau-Stewart C, Castellano L, Green AR, Coombes RC, Ellis IO, Ali S, Lenz HJ, Stebbing J . 6 . Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer . Nature Medicine . 17 . 6 . 715–719 . June 2011 . 10.1038/nm.2351 . 21602804 . 5279914 .
  4. Fazi B, Felsani A, Grassi L, Moles A, D'Andrea D, Toschi N, Sicari D, De Bonis P, Anile C, Guerrisi MG, Luca E, Farace MG, Maira G, Ciafré SA, Mangiola A . 6 . The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors . Oncotarget . 6 . 26 . 22526–22552 . September 2015 . 26188123 . 4673180 . 10.18632/oncotarget.4151 .
  5. Xu Z, Qi X, Zhang X, Yu L . Preoperative serum LMTK3 as a novel biomarker in non-small cell lung cancer . Tumour Biology . 35 . 5 . 5007–5011 . May 2014 . 24510346 . 10.1007/s13277-014-1660-3 . 14656556 .
  6. Lu L, Yuan X, Zhang Q, Zhang H, Shen B . LMTK3 knockdown retards cell growth and invasion and promotes apoptosis in thyroid cancer . Molecular Medicine Reports . 15 . 4 . 2015–2022 . April 2017 . 28260052 . 5364963 . 10.3892/mmr.2017.6262 .
  7. Jiang T, Lu X, Yang F, Wang M, Yang H, Xing N . LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway . FEBS Open Bio . 10 . 10 . 2107–2121 . October 2020 . 32865871 . 7530379 . 10.1002/2211-5463.12964 .
  8. Kawa S, Fujimoto J, Tezuka T, Nakazawa T, Yamamoto T . Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling . Genes to Cells . 9 . 3 . 219–232 . March 2004 . 15005709 . 10.1111/j.1356-9597.2004.00714.x .
  9. Inoue T, Hoshina N, Nakazawa T, Kiyama Y, Kobayashi S, Abe T, Yamamoto T, Manabe T, Yamamoto T . 6 . LMTK3 deficiency causes pronounced locomotor hyperactivity and impairs endocytic trafficking . The Journal of Neuroscience . 34 . 17 . 5927–5937 . April 2014 . 24760852 . 6608282 . 10.1523/JNEUROSCI.1621-13.2014 .
  10. Montrose K, Kobayashi S, Manabe T, Yamamoto T . Lmtk3-KO Mice Display a Range of Behavioral Abnormalities and Have an Impairment in GluA1 Trafficking . Neuroscience . 414 . 154–167 . August 2019 . 31310731 . 10.1016/j.neuroscience.2019.06.033 . 195937172 .
  11. Stebbing J, Filipovic A, Ellis IO, Green AR, D'Silva TR, Lenz HJ, Coombes RC, Wang T, Lee SC, Giamas G . 6 . LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome . Breast Cancer Research and Treatment . 132 . 2 . 537–544 . April 2012 . 21671015 . 10.1007/s10549-011-1622-z . 19222468 .
  12. Stebbing J, Filipovic A, Lit LC, Blighe K, Grothey A, Xu Y, Miki Y, Chow LW, Coombes RC, Sasano H, Shaw JA, Giamas G . 6 . LMTK3 is implicated in endocrine resistance via multiple signaling pathways . Oncogene . 32 . 28 . 3371–3380 . July 2013 . 22869149 . 10.1038/onc.2012.343 .
  13. Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, Wendler F, Simon T, Szabó KS, O'Hanlon T, Dean M, Roslani AC, Cheah SH, Lee SC, Giamas G . 6 . LMTK3 confers chemo-resistance in breast cancer . Oncogene . 37 . 23 . 3113–3130 . June 2018 . 29540829 . 5992129 . 10.1038/s41388-018-0197-0 .
  14. Xu Y, Zhang H, Lit LC, Grothey A, Athanasiadou M, Kiritsi M, Lombardo Y, Frampton AE, Green AR, Ellis IO, Ali S, Lenz HJ, Thanou M, Stebbing J, Giamas G . 6 . The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁ . Science Signaling . 7 . 330 . ra58 . June 2014 . 24939894 . 10.1126/scisignal.2005170 . 7831460 .
  15. Xu Y, Zhang H, Nguyen VT, Angelopoulos N, Nunes J, Reid A, Buluwela L, Magnani L, Stebbing J, Giamas G . 6 . LMTK3 Represses Tumor Suppressor-like Genes through Chromatin Remodeling in Breast Cancer . Cell Reports . 12 . 5 . 837–849 . August 2015 . 26212333 . 10.1016/j.celrep.2015.06.073 . 10044/1/33933 . free .
  16. Ditsiou A, Cilibrasi C, Simigdala N, Papakyriakou A, Milton-Harris L, Vella V, Nettleship JE, Lo JH, Soni S, Smbatyan G, Ntavelou P, Gagliano T, Iachini MC, Khurshid S, Simon T, Zhou L, Hassell-Hart S, Carter P, Pearl LH, Owen RL, Owens RJ, Roe SM, Chayen NE, Lenz HJ, Spencer J, Prodromou C, Klinakis A, Stebbing J, Giamas G . 6 . The structure-function relationship of oncogenic LMTK3 . Science Advances . 6 . 46 . November 2020 . 33188023 . 7673765 . 10.1126/sciadv.abc3099 . 2020SciA....6.3099D .
  17. Agnarelli A, Lauer Betrán A, Papakyriakou A, Vella V, Samuels M, Papanastasopoulos P, Giamas C, Mancini EJ, Stebbing J, Spencer J, Cilibrasi C, Ditsiou A, Giamas G . 6 . The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor . International Journal of Molecular Sciences . 24 . 1 . January 2023 . 865 . 10.3390/ijms24010865 . free . 36614307 . 9821308 .

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