Unraveling the Function of Lemur Tyrosine Kinase 2 Network

Cruz, Daniel Filipe; Farinha, Carlos M.; Swiatecka‐Urban, Agnieszka

doi:10.3389/fphar.2019.00024

Cited by 14 publications

(13 citation statements)

References 76 publications

(156 reference statements)

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“…A variant within LMTK2 , rs11762534, which is also an eQTL for many genes, displays evidence of selection (s=0.005; logLR = 16.49) and is associated with blood cell percentages and malignant neoplasm of prostate. LMTK2 encodes a serine/threonine kinase that is implicated in diverse cellular processes including apoptosis, growth factor signalling and appears essential for spermatogenesis in mice (Kawa et al, 2006; Cruz et al, 2019). Outside the Middle East, the variant is highly stratified and is present at the highest frequency in Europeans (1KG, 45%), but we find it at 66% frequency in the Arabian populations.…”

Section: Resultsmentioning

confidence: 99%

“…We also identified additional variants that show an increase in frequency recently ( Figure 4C-D. A variant within LMTK2, rs11762534, which is also an eQTL for many genes, displays evidence of selection (s=0.005; logLR = 16.49) and is associated with blood cell percentages and malignant neoplasm of prostate. LMTK2 encodes a serine/threonine kinase that is implicated in diverse cellular processes including apoptosis, growth factor signalling and appears essential for spermatogenesis in mice (Kawa et al, 2006;Cruz et al, 2019).…”

Section: Selectionmentioning

confidence: 99%

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The Genomic History of the Middle East

Almarri

Haber

Lootah³

et al. 2020

Preprint

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The Middle East is an important region to understand human evolution and migrations, but is underrepresented in genetic studies. We generated and analysed 137 high-coverage physically-phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations, but find Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. A divergence in population size within the region starts before the Neolithic, when Levantines expanded while Arabians maintained small populations that could have derived ancestry from local epipaleolithic hunter-gatherers. All populations suffered a bottleneck overlapping the archaeologically-documented 4.2 kiloyear aridification of the area, while regional migrations increased genetic structure, and may have contributed to the spread of the Semitic languages. We identify new variants that show evidence of selection, some dating from the onset of the desert climate in the region. Our results thus provide detailed insights into the genomic and selective histories of the Middle East.

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Section: Resultsmentioning

confidence: 99%

Section: Selectionmentioning

confidence: 99%

The Genomic History of the Middle East

Almarri

Haber

Lootah³

et al. 2020

Preprint

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“…This dual role of PP1γ2 is intriguing because loss of the enzymes of cAMP metabolism and action, sAC or PKA in testis, does not impair sperm morphogenesis or sperm formation. It is likely that other serine/threonine protein kinases along with PP1γ2 are responsible for regulation of protein phosphorylation during spermatogenesis (Kawa et al, 2006;Xu et al, 2007;MacLeod et al, 2014;Cruz et al, 2019). Due to its requirement in spermatogenesis, it is not possible to obtain sperm lacking PP1γ2, which is a limitation for the study of the enzyme in mature sperm.…”

Section: Protein Phosphatase Isoform Pp1γ2 In Sperm Functionmentioning

confidence: 99%

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

Dey

Brothag

Vijayaraghavan

2019

Front. Cell Dev. Biol.

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In mammals, motility and fertilizing ability of spermatozoa develop during their passage through the epididymis. After ejaculation, sperm undergo capacitation and hyperactivation in the female reproductive tract-a motility transition that is required for sperm penetration of the egg. Both epididymal initiation of sperm motility and hyperactivation are essential for male fertility. Motility initiation in the epididymis and sperm hyperactivation involve changes in metabolism, cAMP (cyclic adenosine monophosphate), calcium and pH acting through protein kinases and phosphatases. Despite this knowledge, we still do not understand, in biochemical terms, how sperm acquire motility in the epididymis and how motility is altered in the female reproductive tract. Recent data show that the sperm specific protein phosphatase PP1γ2, glycogen synthase kinase 3 (GSK3), and the calcium regulated phosphatase calcineurin (PP2B), are involved in epididymal sperm maturation. The protein phosphatase PP1γ2 is present only in testis and sperm in mammals. PP1γ2 has a isoform-specific requirement for normal function of mammalian sperm. Sperm PP1γ2 is regulated by three proteinsinhibitor 2, inhibitor 3 and SDS22. Changes in phosphorylation of these three inhibitors and their binding to PP1γ2 are involved in initiation and activation of sperm motility. The inhibitors are phosphorylated by protein kinases, one of which is GSK3. The isoform GSK3α is essential for epididymal sperm maturation and fertility. Calcium levels dramatically decrease during sperm maturation and initiation of motility suggesting that the calcium activated sperm phosphatase (PP2B) activity also decreases. Loss of PP2B results in male infertility due to impaired sperm maturation in the epididymis. Thus the three signaling enzymes PP1γ2, GSK3, and PP2B along with the documented PKA (protein kinase A) have key roles in sperm maturation and hyperactivation. Significantly, all these four signaling enzymes are present as specific isoforms only in placental mammals, a testimony to their essential roles in the unique aspects of sperm function in mammals. These findings should lead to a better biochemical understanding of the basis of male infertility and should lead to novel approaches to a male contraception and managed reproduction.

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“…Lemur tyrosine kinase 2 (LMTK2), also 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. Despite its naming, LMTK2 is actually a Ser/Thr kinase that has been identified to interact with a restrict number of proteins, although related to different signaling pathways and key cellular processes [reviewed in (1)]. 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)2, BCL-xL and BCL2-interacting mediator of cell death (BIM) (9).…”

Section: Introductionmentioning

confidence: 99%

Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling

Cruz

Mitash

et al. 2021

Front. Oncol.

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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.

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Unraveling the Function of Lemur Tyrosine Kinase 2 Network

Cited by 14 publications

References 76 publications

The Genomic History of the Middle East

The Genomic History of the Middle East

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling

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