Identification and analysis of mammalian KLK6 orthologue genes for prediction of physiological substrates

Pampalakis, Georgios; Arampatzidou, Maria; Amoutzias, Grigoris D.; Kossida, Sofia; Sotiropoulou, Georgia

doi:10.1016/j.compbiolchem.2007.11.002

Cited by 13 publications

(14 citation statements)

References 41 publications

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“…KLK6 in human, mouse and dog; KLK8 in human and dog; KLK11 in human and mouse), there is no overall conservation of isoform types between species, or between the different kallikreins. Some alternative transcripts which have been reported previously, are not included in the databases used, for example KLK6 alternative transcripts in cattle, which use alternative promoters and differ in the 5′ UTR region [41]. Although this again indicates that similar structural diversity in the 5′UTR of KLK6 is shared between different species, the overall conclusion remains that, by and large, KLK isoform diversity seems to have evolved in a type-specific and species-specific manner.…”

Section: Resultsmentioning

confidence: 97%

Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms

Koumandou

Scorilas

2013

PLoS ONE

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Kallikreins are secreted serine proteases with important roles in human physiology. Human plasma kallikrein, encoded by the KLKB1 gene on locus 4q34-35, functions in the blood coagulation pathway, and in regulating blood pressure. The human tissue kallikrein and kallikrein-related peptidases (KLKs) have diverse expression patterns and physiological roles, including cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis. Prostate-specific antigen (PSA), the product of the KLK3 gene, is the most widely used biomarker in clinical practice today. A total of 15 KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4), which makes them ideal for evolutionary analysis of gene duplication events. Previous studies on the evolution of KLKs have traced mammalian homologs as well as a probable early origin of the family in aves, amphibia and reptilia. The aim of this study was to address the evolutionary and functional relationships between tissue KLKs and plasma kallikrein, and to examine the evolution of alternative splicing isoforms. Sequences of plasma and tissue kallikreins and their alternative transcripts were collected from the NCBI and Ensembl databases, and comprehensive phylogenetic analysis was performed by Bayesian as well as maximum likelihood methods. Plasma and tissue kallikreins exhibit high sequence similarity in the trypsin domain (>50%). Phylogenetic analysis indicates an early divergence of KLKB1, which groups closely with plasminogen, chymotrypsin, and complement factor D (CFD), in a monophyletic group distinct from trypsin and the tissue KLKs. Reconstruction of the earliest events leading to the diversification of the tissue KLKs is not well resolved, indicating rapid expansion in mammals. Alternative transcripts of each KLK gene show species-specific divergence, while examination of sequence conservation indicates that many annotated human KLK isoforms are missing the catalytic triad that is crucial for protease activity.

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Section: Resultsmentioning

confidence: 97%

Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms

Koumandou

Scorilas

2013

PLoS ONE

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“…For the first time, WNT/BMP, IGF and TGF signaling were identified as pathways activated by KLK6 proteolysis (Table 1). The association of KLK6 with the TGF-β pathway was suggested before [39]. Interestingly, perturbations in TGF-β signaling pathway have been involved in the regulation of survival of dopaminergic neurons and the aggregation of α-synuclein [40].…”

Section: Discussionmentioning

confidence: 95%

KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species

et al. 2016

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KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in “a prion-like mechanism”. Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.

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“…Direct cleavage of vimentin by KLK6 is unlikely because KLK6 is an extracellular protease. Construction of the KLK6 interactome revealed that KLK6 might act via the transforming growth factorh1 (TGF-h1) pathway to reduce TGF-h1 levels by degrading the extracellular protein fibronectin (40). Fibronectin increases steadystate mRNA levels of TGF-h1 that is known to up-regulate vimentin and to down-regulate cytokeratin 8 and calreticulin.…”

Section: Discussionmentioning

confidence: 99%

A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

et al. 2009

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Human kallikrein-related peptidase 6 (KLK6) was cloned as a putative class II tumor suppressor based on its inactivated expression in metastatic breast cancer. Here, we investigated the mechanism(s) underlying the silencing of KLK6 gene in metastatic breast cancer and its putative implications for tumor progression. We present evidence that tumor-specific loss of KLK6 expression is due to hypermethylation of specific CpGs located in the KLK6 proximal promoter. Methylationdependent binding of methyl CpG-binding protein 2 and the formation of repressive chromatin mediated by localized histone deacetylation are critical components of KLK6 silencing in breast tumors. Re-expression of KLK6 in nonexpressing MDA-MB-231 breast tumor cells by stable cDNA transfection resulted in marked reversal of their malignant phenotype, manifested by lower proliferation rates and saturation density, marked inhibition of anchorage-independent growth, reduced cell motility, and their dramatically reduced ability to form tumors when implanted in severe combined immunodeficiency mice. Interestingly, inhibition of tumor growth was observed at physiologic concentrations of KLK6, but not when KLK6 was highly overexpressed, as observed in a subset of breast tumors. Differential proteomic profiling revealed that KLK6 re-expression results in significant down-regulation of vimentin which represents an established marker of epithelial-to-mesenchymal transition of tumor cells and in concomitant up-regulation of calreticulin and epithelial markers cytokeratin 8 and 19, indicating that KLK6 may play a protective role against tumor progression that is likely mediated by inhibition of epithelial-to-mesenchymal transition. We suggest that KLK6 is an epigenetically regulated tumor suppressor in human breast cancer and provide ways of pharmacologic modulation. [Cancer Res 2009;69(9):3779-87]

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Identification and analysis of mammalian KLK6 orthologue genes for prediction of physiological substrates

Cited by 13 publications

References 41 publications

Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms

Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms

KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species

A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

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