Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review
Abstract
:1. Introduction
Prostate Cancer
2. LMTK Proteins
2.1. LMTKs and Cancer
2.2. Catalytic Specificity of LMTKs
2.3. Localisation, Membrane Topology and Structural Features of LMTKs
3. Literature Review
3.1. Evidence for LMTK2 Involvement in Prostate Cancer
3.2. Evidence for LMTK3 Involvement in Prostate Cancer
4. Epigallocatechin-3-Gallate
5. Discussion
6. Methods: Search Strategy and Study Selection
Author Contributions
Funding
Conflicts of Interest
References
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Entry Name | Protein Names | Gene Names | Length (Res.) | Proton Acceptor Active Site | ATP Binding Site | ATP Nucleotide Binding (Res. Number) |
---|---|---|---|---|---|---|
LMTK1_HUMAN | Serine/threonine-protein kinase LMTK1, (EC 2.7.11.1) (Apoptosis-associated tyrosine kinase) (AATYK) (Brain apoptosis-associated tyrosine kinase) (CDK5-binding protein) (Lemur tyrosine kinase 1) (p35-binding protein) (p35BP) | AATK, AATYK, KIAA0641, LMR1, LMTK1 | 1374 | D253 | K156 | 131–139 |
LMTK2_HUMAN | Serine/threonine-protein kinase LMTK2, (EC 2.7.11.1) (Apoptosis-associated tyrosine kinase 2) (Brain-enriched kinase) (hBREK) (CDK5/p35-regulated kinase) (CPRK) (Kinase/phosphatase/inhibitor 2) (Lemur tyrosine kinase 2) (Serine/threonine-protein kinase KPI-2) | LMTK2, AATYK2, BREK, KIAA1079, KPI2, LMR2 | 1503 | D265 | K168 | 143–151 |
LMTK3_HUMAN | Serine/threonine-protein kinase LMTK3 (EC 2.7.11.1) (Lemur tyrosine kinase 3) | LMTK3, KIAA1883, TYKLM3 | 1460 | D266 | K164 | 139–147 |
Reference | Cell Line/Tissue | Principal Techniques | Main Results | Conclusions |
---|---|---|---|---|
Harries et al. [60] | Human prostate samples (cancer and benign prostatic hyperplasia, BPH) from Exeter tissue bank | PCR amplification and sequencing for genotyping 7 GWAS risk loci | Risk genotype at the GWAS variant rs6465657 correlates with LMTK2 expression | Expression levels of LMTK2 inversely correlate with the presence of prostate cancer |
Real-time PCR | Prostate adenocarcinoma samples expressed 68% less LMTK2 mRNA than BPH samples | |||
Vezelis et al. [61] | Blood sample of patients who had rising PSA after negative transrectal systematic prostate biopsy | Analysis of CRISP3, LMTK2 and MSMB gene expression by means of quantitative RT-PCR | LMTK2 and MSMB expression significantly decreases in blood samples of patients with PCa and Benign Prostate Disease as compared to control PSA density (ng/mL) can differentiate PCa from the benign prostate disease | PSA density, in combination with LMTK2 expression level, may assist in stratification between clinically insignificant and clinically significant PCa |
Shah et al. [57] | Human prostate tissue array (prostate cancer, hyperplasia, and normal prostate tissue) | Immunostaining analysis | LMTK2 is down regulated in human PCa | Loss of LMTK2 protein is strongly associated with prostate cancer and prostate hyperplasia LMTK2 interacts directly with AR and inhibits its transcriptional activity LMTK2 down-regulation promotes tumour forming capacity and proliferation The decrease in LMTK2 expression in prostate cancer patient may promote tumour cells proliferation by enhancing AR transcriptional activity |
LNCaP cells Normal human prostate tissue | Coimmunoprecipitation Colocalisation analysis by immunostaining | LMTK2 and AR interact in prostate cancer cells and colocalise in human prostate tissue | ||
HEK293 cells | Dual luciferase assay with LMTK2 knockdown or LMTK2 overexpression | Knockdown of LMTK2 in cells expressing AR enhances androgen-dependent activation of a luciferase reporter gene Overexpression of LMTK2 in cells expressing AR decreases androgen-dependent activation of a luciferase reporter gene | ||
LNCaP cells | Real-time PCR | LMTK2 knockdown cells, deprived from androgens, show a significant increase in mRNA expression of AR responsive genes | ||
LNCaP cells | Tumoursphere assay Cell viability assay | LNCaP knockdown cells: -showed higher colony-forming capacity -showed ~5 times higher cell viability under androgen starvation | ||
Puri et al. [66] | LNCaP cells | Immunofluorescence microscopy | Myosin VI is present on early endosomes, recycling endosomes and trans-Golgi network | LMTK2, together with Myosin VI, may participate in the orchestration of endosomal recycling pathway The secretory pathway via the recycling endosome can be involved in PCa pathology |
Coimmunoprecipitation | LMTK2 binds to and coimmunoprecipitates with Myosin VI | |||
Myosin VI siRNA knockdown | Secretion of PSA and VEGF is reduced | |||
Manser et al. [67] | HeLa cells | Coimmunoprecipitation Immunoblot analysis | LMTK2 interacts with Protein Phosphatase-1C LMTK2 increases inhibitory phosphorylation of Glycogen Synthase Kinase-3β LMTK2 reduces Kinesin-1-Light Chain 2 phosphorylation and promotes KLC2 binding of Smad2 transcription factor | Since LMTK2 expression is significantly reduced in prostate cancer tissues, Smad2 binding to KLC2 and transport on Kinesin-1 may also be inhibited in prostate cancer cells |
siRNA knockdown of LMTK2 | LMTK2 knockdown inhibits Smad2 nuclear signalling in response to TGF-β receptor activation |
Reference | Cell Line/Tissue | Principal Techniques | Main Results | Conclusions |
---|---|---|---|---|
Sun et al. [68] | Prostate cancer tissue | Quantitative RT-PCR Immunoblot analysis data | Expression of LMTK3 is reduced as compared to normal tissue | A low level of LMTK3 expression is associated with PCa LMTK3 overexpression can induce PCa apoptosis in vitro and in vivo, and Akt and MAPK signalling pathways may contribute to this process Low levels of LMTK3 ex-pression in PCa tissue may reflect a decreased apoptotic rate |
PC3 and LNCaP prostate cancer cells infected with recombinant lentivirus-LMTK3 | MTT and TUNEL assays Transwell and Matrigel invasion assays Immunoblot analysis | Overexpression of LMTK3:
| ||
Subcutaneous tumour model in nude mice, based on PC3 cells infected with recombinant lentivirus-LMTK3 | Caliper measurement TUNEL assay Immunoblot analysis | Overexpression of LMTK3:
| ||
Gao et al. [70] | DU145 prostate cancer cells | Reverse transfection with a kinase siRNA library Exposition to IGFIR1 AZ12253801 inhibitor | AZ12253801 inhibits IGFIR phosphorylation and cell viability LMTK3 depletion enhances AZ12253801 sensitivity | LMTK3 is among the putative mediators of resistance to IGFIR inhibition |
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Ferrari, E.; Naponelli, V.; Bettuzzi, S. Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review. Int. J. Mol. Sci. 2021, 22, 5453. https://doi.org/10.3390/ijms22115453
Ferrari E, Naponelli V, Bettuzzi S. Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review. International Journal of Molecular Sciences. 2021; 22(11):5453. https://doi.org/10.3390/ijms22115453
Chicago/Turabian StyleFerrari, Elena, Valeria Naponelli, and Saverio Bettuzzi. 2021. "Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review" International Journal of Molecular Sciences 22, no. 11: 5453. https://doi.org/10.3390/ijms22115453