Abstract
Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-β1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-β1 dependent or independent manner. To understand how the LMTK2 and TGF-β1 pathways interconnect, we knocked down (KD) LMTK2 using small(si)RNA-mediated silencing in human bronchial epithelial CFBE41o- cells, treated cells with TGF-β1 or vehicle control, and performed differential gene expression analysis by RNA sequencing (RNAseq). In vehicle-treated cells, LMTK2 KD affected expression of 2,506 genes while it affected 4,162 genes after TGF-β1 stimulation. Bioinformatics analysis shows that LMTK2 is involved in diverse cellular functions and disease pathways, such as cell death and survival, cellular development, and cancer susceptibility. In summary, our study increases current knowledge about the LMTK2 network and its intersection with the TGF-β1 signaling pathway. These findings will serve as basis for future exploration of the predicted LMTK2 interactions and signaling pathways.
Highlights
Lemur tyrosine kinase 2 (LMTK2), known as cyclin-dependent kinase-5 (CDK5)/p35 regulated kinase, kinase/phosphatase/inhibitor-2 (KPI2), brain-enriched kinase (BREK), and apoptosis-associated tyrosine kinase (AATYK)-2, is a member of the lemur family of membraneanchored kinases
CFBE41o- cells were transfected with siRNA targeting human LMTK2 gene (siLMTK2) or non-targeting siRNA (siCTRL) and LMTK2 protein abundance was assessed by western blotting (WB)
Total RNA was isolated, from CFBE41o- cells transfected with siLMTK2 or siCTRL and treated with transforming growth factor b1 (TGF-b1) or vehicle control for 24h, using the Quick-RNATM MiniPrep kit (Zymo Research), and analyzed on the Illumina platform
Summary
Lemur tyrosine kinase 2 (LMTK2), known as cyclin-dependent kinase-5 (CDK5)/p35 regulated kinase (cprk), kinase/phosphatase/inhibitor-2 (KPI2), brain-enriched kinase (BREK), and apoptosis-associated tyrosine kinase (AATYK)-2, is a member of the lemur family of membraneanchored kinases. Earlier studies have shown that LMTK2 interacts with CDK5 and protein phosphatase 1 (PP1c) [2,3,4,5], cystic fibrosis transmembrane conductance regulator (CFTR) [6], myosin VI [7, 8], and anti- and pro-apoptotic proteins, such as B-cell lymphoma (BCL), BCL-xL and BCL2-interacting mediator of cell death (BIM) [9] These protein-protein interactions indicate that LMTK2 plays a role in diverse cellular functions, including protein transcription, intracellular protein trafficking, cell differentiation, and apoptosis [6,7,8,9,10]. The role of LMTK2 in endocytic trafficking was supported by its interactions with myosin VI found to be necessary for transport of the transferrin receptor from early endosomes to the recycling vesicles [7, 8]
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