Protects against mitochondrial dysfunction during cellular stress, potentially by phosphorylating mitochondrial proteins. Involved in the clearance of damaged mitochondria via selective autophagy (mitophagy). It is necessary for PARK2 recruitment to dysfunctional mitochondria to initiate their degradation.
Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (DeltaPsi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Interacting selectively and non-covalently with a C3HC4-type zinc finger domain of a protein. The C3HC4-type zinc finger is a variant of RING finger, is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C, where X is any amino acid. Many proteins containing a C3HC4-type RING finger play a key role in the ubiquitination pathway.
Evidence
1:
Inferred from Physical InteractionBHF-UCL
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Several mutations in PTEN-induced putative kinase 1 (PINK1) gene have been reported to be associated with recessive parkinsonism. The encoded protein is predicted to be a Ser/Thr protein kinase targeted to mitochondria. In this study, we have investigated the effects of mutations on PINK1 kinase activity in vitro and on expression levels and localization in mammalian cells. We chose to examine two point mutations: G309D, which was originally reported to be stable and properly localized in cells and L347P, which is of interest because it is present at an appreciable carrier frequency in the Philippines. We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. The L347P mutation grossly destabilizes PINK1 and drastically reduces kinase activity, whereas G309D has much more modest effects on these parameters in vitro. This finding is in line with predictions based on homology modeling. We also examined the localization of PINK1 in transfected mammalian cells by using constructs that were tagged with myc or GFP at either end of the protein. These results show that PINK1 is processed at the N terminus in a manner consistent with mitochondrial import, but the mature protein also exists in the cytosol. The physiological relevance of this observation is not yet clear, but it implies that a portion of PINK1 may be exported after processing in the mitochondria.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson's disease proteins, the Ser/Thr kinase PINK1 and ubiquitin ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin, but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
Any biological process that results in permanent cessation of all vital functions of a cell. A cell should be considered dead when any one of the following molecular or morphological criteria is met: (1) the cell has lost the integrity of its plasma membrane; (2) the cell, including its nucleus, has undergone complete fragmentation into discrete bodies (frequently referred to as \
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a toxin stimulus.
A series of reactions in which a signal is passed on to downstream proteins within the cell by sequential protein phosphorylation and activation of the cascade components.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Any process that increases the rate, frequency or extent of release of cytochrome c from mitochondria, the process in which cytochrome c is enabled to move from the mitochondrial intermembrane space into the cytosol, which is an early step in apoptosis and leads to caspase activation.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Any process that activates, maintains or increases the frequency, rate or extent of dopaminergic synaptic transmission, the process of communication from a neuron to another neuron across a synapse using the neurotransmitter dopamine.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. We find that phosphorylation of parkin by PINK1 activates parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhances parkin-mediated ubiquitin signaling through the IkappaB kinase/nuclear factor kappaB (NF-kappaB) pathway. Furthermore, the ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling is impaired by PD-linked pathogenic PINK1 mutations. Our findings support a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicate the deregulation of the PINK1/parkin/NF-kappaB neuroprotective signaling pathway in the pathogenesis of PD.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a disturbance in organismal or cellular homeostasis, usually, but not necessarily, exogenous (e.g. temperature, humidity, ionizing radiation).
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
A novel protein kinase named BRPK was isolated and partially characterized. BRPK was expressed at a higher level in three carcinoma cell lines with higher metastatic potential. Mouse and human BRPK cDNAs are well conserved and encode 580 and 581 amino acids, respectively. BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. The results of a comparative sequence analysis indicated a possible link of BRPK to BRAP2. BRAP2 is known to bind the nuclear localization signal of BRCA1. We cloned mouse BRAP2 cDNA and showed the presence of isoforms.
Protein participating in autophagy, a process of intracellular bulk degradation in which cytoplasmic components including organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for degradation. There are three primary forms of autophagy: chaperone-mediated autophagy, microautophagy and macroautophagy. During macroautophagy, the sequestering vesicles, termed autophagosomes, fuse with the lysosome or vacuole resulting in the delivery of an inner vesicle (autophagic body) into the lumen of the degradative compartment.
Protein which catalyzes the phosphorylation of serine or threonine residues on target proteins by using ATP as phosphate donor. Such phosphorylation may cause changes in the function of the target protein. Protein kinases share a conserved catalytic core common to both serine/ threonine and tyrosine protein kinases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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