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malfunction
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ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line is reduced by lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, which reduces the neurotoxic effects of the enzyme
malfunction
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KLK6 knockout mice have thinner epidermis and decreased keratinocyte proliferation. The keratinocytes in wild type and KLK6 knockout epidermis are equally sensitive to acute anti-proliferative effect of fluocinolone acetonide. The development of proliferative resistance during chronic treatment is reduced in knockout epidermis
metabolism
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kallikrein 6 and thrombin are important regulators of neural pathophysiology and neurotoxic
metabolism
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mechanism of epidermal regeneration after glucocorticoid-induced atrophy via KLK6 activation
physiological function
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KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of protease-activated receptor 1. Recombinant KLK6 significantly reduces cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Immune cell survival promoting effects of KLK6 include both T and B lymphocytes and involve up regulation of the pro-survival protein B-cell lymphoma-extra large and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death
physiological function
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involvement of Klk6 in chronic progressive demyelinating disease, regulatory activities for kallikrein 6 in the development and progression of central nervous system inflammation and demyelination, overview
physiological function
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kallikrein 6 is a serine protease implicated in neurodegeneration. Kallikrein 6 elicits ERK1/2 signaling in neurons by activation of protease activated receptors PAR1 and PAR2. Recombinant Klk6 triggered ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a PI3K and MEK-dependent fashion. Kallikrein 6 and thrombin promote degeneration of cerebellar neurons and exacerbate glutamate neurotoxicity
physiological function
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the enzyme activates G-protein coupled protease activated receptors. The enzyme serves as a molecular trigger of selected physiological processes involved in the development of astrogliosis and causes astrocytes to transform from an epitheliod to a stellate morphology and to secrete interleukin 6. It reduces expression of glial fibrillary acidic protein. Injury-induced elevations in enzyme level contribute to the development of astrogliosis in a protease activated receptor-dependent fashion. The enzyme stellation promoting activity is dependent on activation of the thrombin receptor, PAR1, the enzyme effects are blocked by the PAR1 specific inhibitor SCH79797. The kallikrein 6-induced astrocyte stellation is mediated by protein kinase C. Kallikrein 6 activates PAR1 in neurons and PAR1 and PAR2 in astrocytes to elicit intracellular Ca2+ flux and regulation of the mitogen activated protein kinase (MAPK) signaling pathway
physiological function
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the enzyme can influence astrocyte plasticity through receptor-dependent mechanisms. Recombinant Klk6 evokes increases in intracellular Ca2+ in primary astrocyte monolayer cultures through activation of proteinase activated receptor 1 (PAR1). Klk6 promotes a condensation of astrocyte cortical actin leading to an elongated stellate shape and multicellular aggregation in a manner that is dependent on the presence of either PAR1 or PAR2. Klk6-evoked changes in astrocyte shape are accompanied by translocation of beta-catenin from the plasma membrane to the cytoplasm
additional information
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Klk6 and the prototypical activator of protease activated receptor 1, PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury at acute or subacute time points
additional information
brain-targeted neurosin accumulates throughout the CNS in neurons, astrocytes and microglia, and results in reduced accumulation of alpha-synuclein in oligodendrocytes and astrocytes with possible clearance via microglia. It also ameliorates myelin degeneration, neuropathology and behavioral deficits. The modified, brain-targeted neurosin may warrant further investigation as potential therapy for multiple system atrophy
additional information
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brain-targeted neurosin accumulates throughout the CNS in neurons, astrocytes and microglia, and results in reduced accumulation of alpha-synuclein in oligodendrocytes and astrocytes with possible clearance via microglia. It also ameliorates myelin degeneration, neuropathology and behavioral deficits. The modified, brain-targeted neurosin may warrant further investigation as potential therapy for multiple system atrophy
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Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.
The SWISS-PROT protein knowledgebase and its supplement TrEMBL
Nucleic Acids Res.
31
365-370
2003
Homo sapiens (Q92876), Mus musculus (P15947)
brenda
Yamaguchi, N.
Neurosin or human kallikrein 6
Handbook of proteolytic enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , eds. ) Academic Press
2
1585-1587
2004
Homo sapiens, Mus musculus, Rattus norvegicus
-
brenda
Klucky, B.; Mueller, R.; Vogt, I.; Teurich, S.; Hartenstein, B.; Breuhahn, K.; Flechtenmacher, C.; Angel, P.; Hess, J.
Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion
Cancer Res.
67
8198-8206
2007
Homo sapiens (Q92876), Homo sapiens, Mus musculus
brenda
Bando, Y.; Ito, S.; Nagai, Y.; Terayama, R.; Kishibe, M.; Jiang, Y.P.; Mitrovic, B.; Takahashi, T.; Yoshida, S.
Implications of protease M/neurosin in myelination during experimental demyelination and remyelination
Neurosci. Lett.
405
175-180
2006
Mus musculus, Mus musculus BALB/c
brenda
Pampalakis, G.; Arampatzidou, M.; Amoutzias, G.; Kossida, S.; Sotiropoulou, G.
Identification and analysis of mammalian KLK6 orthologue genes for prediction of physiological substrates
Comput. Biol. Chem.
32
111-121
2008
Bos taurus (A6QQ95), Bos taurus, Canis lupus familiaris, Homo sapiens (Q92876), Homo sapiens, Macaca mulatta, Mus musculus, Pan troglodytes, Rattus norvegicus, Sus scrofa
brenda
Scarisbrick, I.A.; Epstein, B.; Cloud, B.A.; Yoon, H.; Wu, J.; Renner, D.N.; Blaber, S.I.; Blaber, M.; Vandell, A.G.; Bryson, A.L.
Functional role of kallikrein 6 in regulating immune cell survival
PLoS ONE
6
e18376
2011
Homo sapiens, Mus musculus
brenda
Scarisbrick, I.A.; Radulovic, M.; Burda, J.E.; Larson, N.; Blaber, S.I.; Giannini, C.; Blaber, M.; Vandell, A.G.
Kallikrein 6 is a novel molecular trigger of reactive astrogliosis
Biol. Chem.
393
355-367
2012
Mus musculus
brenda
Scarisbrick, I.A.; Yoon, H.; Panos, M.; Larson, N.; Blaber, S.I.; Blaber, M.; Rodriguez, M.
Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis
Brain Pathol.
22
709-722
2012
Homo sapiens (Q92876), Mus musculus, Mus musculus SJL/J
brenda
Yoon, H.; Radulovic, M.; Wu, J.; Blaber, S.I.; Blaber, M.; Fehlings, M.G.; Scarisbrick, I.A.
Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity
J. Neurochem.
127
283-298
2013
Mus musculus, Mus musculus C57/BL6J
brenda
Yoon, H.; Scarisbrick, I.A.
Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
Biol. Chem.
397
1277-1286
2016
Mus musculus
brenda
Yoon, H.; Radulovic, M.; Scarisbrick, I.A.
Kallikrein-related peptidase 6 orchestrates astrocyte form and function through proteinase activated receptor-dependent mechanisms
Biol. Chem.
399
1041-1052
2018
Mus musculus
brenda
Spencer, B.; Valera, E.; Rockenstein, E.; Trejo-Morales, M.; Adame, A.; Masliah, E.
A brain-targeted, modified neurosin (kallikrein-6) reduces alpha-synuclein accumulation in a mouse model of multiple system atrophy
Mol. Neurodegener.
10
48
2015
Mus musculus (Q91Y82), Mus musculus
brenda
Kishibe, M.; Baida, G.; Bhalla, P.; Lavker, R.M.; Schlosser, B.; Iinuma, S.; Yoshida, S.; Dudley, J.T.; Budunova, I.
Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids
Oncotarget
7
69479-69488
2016
Mus musculus
brenda