The multifaceted role of lemur tyrosine kinase 3 in health and disease

Abstract

In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, there is mounting evidence that LMTK3 promotes oncogenesis in a wide variety of cancers. Recent studies have broadened our understanding of LMTK3 and demonstrated its importance in numerous signalling pathways, culminating in the identification of a potent and selective LMTK3 inhibitor. Here, we review the roles of LMTK3 in health and disease and discuss how this research may be used to develop novel therapeutics to advance cancer treatment.

Keywords: CNS; LMTK3; cancer; protein kinase; small molecule kinase inhibitor.

Figure 1.

LMTK3 impacts on several facets of tumorigenesis. Graphical summary of the main mechanisms of oncogenic LMTK3 signalling. (a) ERα regulation by LMTK3. LMTK3 regulates the activity of ERα at both the mRNA and protein level. LMTK3 reduces the activity of PKC, resulting in decreased levels of phosphorylated AKT and increased binding of FOXO3 to the ESR1 promoter, indirectly increasing transcription of ERα. In addition, LMTK3 directly phosphorylates ERα, promoting stability by protecting it from ubiquitin-mediated proteasomal degradation. Adapted from Johnson & O'Malley [19,80]. (b) LMTK3 stability. Like many other oncogenic protein kinases, LMTK3 has recently been identified as an HSP90–CDC37 client protein requiring HSP90 for its folding and stability [33]. (c) The chromatin remodelling and transcriptional co-repressor behaviour of LMTK3. LMTK3 binds PP1α and KAP1, promoting KAP1 Ser⁸²⁴ dephosphorylation, which results in chromatin condensation. Meanwhile, LMTK3 acts as a scaffolding protein, tethering the heterochromatin complex to the nuclear lamina. In doing so, LMTK3 promotes transcriptional repression of tumour suppressor-like genes. Adapted from Xu et al. [29]. (d) The role of LMTK3 in proliferation, invasion and migration. LMTK3 increases the abundance of integrin α5β1 by interacting with the adaptor protein GRB2. This interaction recruits SOS1, promoting the activation of Ras and CDC42. This increases the activity of the transcription factor SRF, leading to increased binding at the ITGA5 and ITGB1 promoters, resulting in integrin α5 and β1 upregulation [27]. (e) LMTK3 promotes cell–cell repulsion through phosphorylation of RCP. Phosphorylation of RCP by LMTK3 has been shown to be required for the trafficking of EphA2 to the membrane via Rab14-positive endosomes. This phosphorylation event is therefore important in driving tumour dissemination through contributing to cell–cell repulsion [28]. AKT/PKB, protein kinase B; CDC37, cell division cycle 37; CDC42, cell division cycle 42; EphA2, ephrin type-A receptor 2; ERα, oestrogen receptor alpha; ESR1, oestrogen receptor 1; FOXO3, forkhead box O3; GRB2, growth factor receptor-bound protein 2; HSPB1, heat shock protein beta-1; HSP90, heat shock protein 90; ITGA5, integrin subunit alpha 5; ITGB1, integrin subunit beta 1; KAP1, Krüppel-associated box domain-associated protein 1; LMTK3, lemur tyrosine kinase 3; PKC, protein kinase C; PP1α, protein phosphatase 1α; Rab14, Ras-related protein Rab14; RCP, Rab-coupling protein; SOS1, son of sevenless homologue 1; SRF, serum response factor.

Figure 2.

LMTK3-mediated endocrine and cytotoxic drug resistance in breast cancer. An increased LMTK3 abundance confers endocrine and chemotherapy resistance in breast cancer. Interestingly, LMTK3 differentially regulates genes in the presence of tamoxifen or doxorubicin. Upon treatment, cells overexpressing LMTK3 modulate the expression of certain genes in the opposite direction to wild-type cells. For example, in wild-type MCF7 cells, HEY1 is upregulated and SOX6 is downregulated when the cells are treated with doxorubicin; however, this is reversed in MCF7 cells overexpressing LMTK3. LMTK3 also modulates the expression of genes involved in tamoxifen resistance, including c-MYC, HSPB8, HEY2 and SIAH2. c-MYC, proto-oncogene c-MYC; HEY1, hairy/enhancer-of-split related with YRPW motif protein 1; HEY2, hairy/enhancer-of-split related with YRPW motif protein 2; HSPB8, heat shock protein beta-8; LMTK3, lemur tyrosine kinase 3; SIAH2, siah E3 ubiquitin-protein ligase 2; SOX6, SRY-box transcription factor 6.

Figure 3.

The mechanism of action of C28. LMTK3 has emerged as a critical mediator of oncogenic functions and is therefore considered to be a promising target of anti-cancer therapies. The small molecule C28 was recently identified as a potent and selective LMTK3 inhibitor. C28 acts by inducing the proteasome-mediated degradation of LMTK3 through chaperone deprivation. Furthermore, the depletion of LMTK3 by C28 results in microtubule instability with subsequent G2/M cell cycle arrest and cell death through downregulating NUSAP1 and the NUSAP1-regulated protein CDK1. This also reduces the phosphorylation of βIII tubulin at Ser¹⁷² [33,34]. CDK1, cyclin-dependent kinase 1; LMTK3, lemur tyrosine kinase 3; NUSAP1, nucleolar and spindle associated protein 1.