PINK1 (PTEN-induced kinase 1) is a mitochondrially targeted Ser/Thr protein kinase. Mutations in PINK1 cause autosomal recessive early-onset Parkinson disease (PARK6). PINK1 has an N-terminal mitochondrial targeting sequence, a single transmembrane segment and a C-terminal kinase domain with distinctive inserts. It acts as a sensor of mitochondrial damage. In healthy, polarized mitochondria the PINK1 precursor is imported through TOM/TIM23 and cleaved by MPP and the inner-membrane rhomboid protease PARL. The resulting fragment is released to the cytosol and degraded by the proteasome, so steady-state levels are very low. When import is blocked by loss of membrane potential or protein misfolding, full-length PINK1 accumulates at the TOM complex on the outer membrane with its kinase domain facing the cytosol, dimerizes and autophosphorylates. It then phosphorylates ubiquitin at Ser65 (including ubiquitin already conjugated to outer-membrane proteins) and Ser65 in the ubiquitin-like domain of the E3 ligase Parkin (PRKN). Phospho-ubiquitin recruits Parkin and, together with Ubl phosphorylation, relieves Parkin autoinhibition. The resulting feed-forward loop coats damaged mitochondria with phospho-ubiquitin chains that recruit autophagy receptors (OPTN, NDP52/CALCOCO2), leading to mitophagy. PINK1 also phosphorylates other substrates, including the mitochondrial chaperone TRAP1, the Miro GTPases (arresting mitochondrial transport) and DRP1 (Ser616, promoting fission). It contributes to mitochondria-derived vesicle trafficking and has broad neuroprotective, anti-apoptotic effects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:14607334 BRPK, a novel protein kinase showing increased expression in... | ACCEPT | Summary: Mg2+ is the divalent cation cofactor for PINK1-catalysed phosphotransfer. Reason: Consistent with its protein kinase activity (in vitro autophosphorylation in Mg2+-containing buffer). Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000107 | ACCEPT | Summary: Mg2+ is the divalent cation cofactor for PINK1-catalysed phosphotransfer. Reason: Consistent with its protein kinase activity (in vitro autophosphorylation in Mg2+-containing buffer). Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PINK1 is the upstream kinase of PINK1/Parkin-mediated mitophagy. It accumulates on depolarized mitochondria and recruits and activates Parkin, and PD-associated PINK1 mutations compromise mitophagy. Reason: Core process, supported by multiple IMP studies and the IBA. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. PMID:24896179 Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. |
| GO:0000422 autophagy of mitochondrion | IMP PMID:20798600 The PINK1/Parkin-mediated mitophagy is compromised by PD-ass... | ACCEPT | Summary: PINK1 is the upstream kinase of PINK1/Parkin-mediated mitophagy. It accumulates on depolarized mitochondria and recruits and activates Parkin, and PD-associated PINK1 mutations compromise mitophagy. Reason: Core process, supported by multiple IMP studies and the IBA. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. PMID:24896179 Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. |
| GO:0000422 autophagy of mitochondrion | IMP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: PINK1 is the upstream kinase of PINK1/Parkin-mediated mitophagy. It accumulates on depolarized mitochondria and recruits and activates Parkin, and PD-associated PINK1 mutations compromise mitophagy. Reason: Core process, supported by multiple IMP studies and the IBA. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. PMID:24896179 Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. |
| GO:0000422 autophagy of mitochondrion | IMP PMID:24896179 The mitochondrial deubiquitinase USP30 opposes parkin-mediat... | ACCEPT | Summary: PINK1 is the upstream kinase of PINK1/Parkin-mediated mitophagy. It accumulates on depolarized mitochondria and recruits and activates Parkin, and PD-associated PINK1 mutations compromise mitophagy. Reason: Core process, supported by multiple IMP studies and the IBA. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. PMID:24896179 Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. |
| GO:0000423 mitophagy | IDA PMID:38081847 GRAF1 integrates PINK1-Parkin signaling and actin dynamics t... | ACCEPT | Summary: PINK1 initiates ubiquitin-dependent mitophagy of damaged mitochondria. Reason: Core process. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:33406421 Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. |
| GO:0000423 mitophagy | IEA GO_REF:0000107 | ACCEPT | Summary: PINK1 initiates ubiquitin-dependent mitophagy of damaged mitochondria. Reason: Core process. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:33406421 Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. |
| GO:0000423 mitophagy | IGI PMID:33406421 OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-... | ACCEPT | Summary: PINK1 initiates ubiquitin-dependent mitophagy of damaged mitochondria. Reason: Core process. Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:33406421 Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. |
| GO:0000785 chromatin | IDA PMID:24798695 PARK13 regulates PINK1 and subcellular relocation patterns u... | KEEP AS NON CORE | Summary: One study reported PINK1 relocating to nuclear/chromatin fractions in neuronal cells under oxidative stress together with PARK13/HtrA2. Reason: Unusual locations from a single study; not where PINK1 performs its established functions. Supporting Evidence: PMID:24798695 We show that PARK13 localizes to a variety of subcellular locations in neuronal cells and that PINK1, although more restrictive, also localizes to locations other than those previously reported. |
| GO:0002020 protease binding | IPI PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | KEEP AS NON CORE | Summary: PINK1 binds the inner-membrane rhomboid protease PARL, which cleaves it. Reason: PINK1 is the protease substrate; the binding is real but not an activity of PINK1. Supporting Evidence: PMID:21138942 Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) |
| GO:0002020 protease binding | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | KEEP AS NON CORE | Summary: PINK1 binds the inner-membrane rhomboid protease PARL, which cleaves it. Reason: PINK1 is the protease substrate; the binding is real but not an activity of PINK1. Supporting Evidence: PMID:21138942 Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) |
| GO:0002082 regulation of oxidative phosphorylation | IDA PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | KEEP AS NON CORE | Summary: PINK1 silencing reduced ATP synthesis. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:20871098 Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. |
| GO:0002931 response to ischemia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred response to ischemia. Reason: Ortholog-transferred (Ensembl Compara) annotation, most likely from a rodent phenotype or expression study. PINK1 loss causes broad mitochondrial dysfunction, so many stress and physiological readouts change secondarily. That does not show PINK1 performs a step of this process. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: PINK1 is a protein kinase whose activity is regulated by autophosphorylation. Reason: Correct; protein serine/threonine kinase activity is more specific. Supporting Evidence: PMID:25527497 Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0004672 protein kinase activity | IMP PMID:25527497 PINK1 kinase catalytic activity is regulated by phosphorylat... | ACCEPT | Summary: PINK1 is a protein kinase whose activity is regulated by autophosphorylation. Reason: Correct; protein serine/threonine kinase activity is more specific. Supporting Evidence: PMID:25527497 Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0004672 protein kinase activity | IMP PMID:32047033 Decision between mitophagy and apoptosis by Parkin via VDAC1... | ACCEPT | Summary: PINK1 is a protein kinase whose activity is regulated by autophosphorylation. Reason: Correct; protein serine/threonine kinase activity is more specific. Supporting Evidence: PMID:25527497 Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:24751536 PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquit... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:24784582 Ubiquitin is phosphorylated by PINK1 to activate parkin. | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:25474007 Phosphorylation of mitochondrial polyubiquitin by PINK1 prom... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:14607334 BRPK, a novel protein kinase showing increased expression in... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:17579517 PINK1 protects against oxidative stress by phosphorylating m... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:24784582 Ubiquitin is phosphorylated by PINK1 to activate parkin. | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:25527291 Ubiquitin Ser65 phosphorylation affects ubiquitin structure,... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-9834076 | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-9835011 | ACCEPT | Summary: PINK1 is a Ser/Thr kinase that phosphorylates ubiquitin and Parkin at Ser65 (and Miro, TRAP1, DRP1). Reason: Core molecular function, supported by direct biochemistry and the IBA. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain PMID:25474007 Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. PMID:24784582 PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. |
| GO:0005515 protein binding | IPI PMID:16632486 Association of PINK1 and DJ-1 confers digenic inheritance of... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:17579517 PINK1 protects against oxidative stress by phosphorylating m... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:20153330 PINK1 is recruited to mitochondria with parkin and associate... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:20153330 PINK1 is recruited to mitochondria with parkin and associate... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:22078885 PINK1 and Parkin target Miro for phosphorylation and degrada... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:24357652 Cytosolic cleaved PINK1 represses Parkin translocation to mi... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:24475098 BAG5 protects against mitochondrial oxidative damage through... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25814554 Phospho-tyrosine dependent protein-protein interaction netwo... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:35391620 The role of the individual TOM subunits in the association o... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:37160114 TIM23 facilitates PINK1 activation by safeguarding against O... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:38848361 Mechanism of human PINK1 activation at the TOM complex in a ... | REMOVE | Summary: Protein-protein interaction (e.g. with Parkin, TRAP1, DJ-1, BAG5, PARL, TOM complex subunits, HSP90/CDC37, or high-throughput interactome partners). Reason: Generic protein binding is uninformative. The informative PINK1 activities are captured by protein serine/threonine kinase activity on ubiquitin and Parkin. Removal does not imply the interactions are false. |
| GO:0005524 ATP binding | IDA PMID:14607334 BRPK, a novel protein kinase showing increased expression in... | ACCEPT | Summary: PINK1 is an ATP-dependent Ser/Thr protein kinase; ATP binding is intrinsic to its catalytic activity. Reason: Supported by kinase/autophosphorylation assays and the conserved kinase domain. Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: PINK1 is an ATP-dependent Ser/Thr protein kinase; ATP binding is intrinsic to its catalytic activity. Reason: Supported by kinase/autophosphorylation assays and the conserved kinase domain. Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0005634 nucleus | IDA PMID:24798695 PARK13 regulates PINK1 and subcellular relocation patterns u... | KEEP AS NON CORE | Summary: Reported nuclear localization of PINK1 in neuronal cells under stress (single study). Reason: Unusual, non-core location. Supporting Evidence: PMID:24798695 We show that PARK13 localizes to a variety of subcellular locations in neuronal cells and that PINK1, although more restrictive, also localizes to locations other than those previously reported. |
| GO:0005737 cytoplasm | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | ACCEPT | Summary: PINK1 is found in the cytoplasm, on mitochondria and as a cleaved cytosolic pool. Reason: Correct, broad location. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:15087508 Hereditary early-onset Parkinson's disease caused by mutatio... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:15824318 Mutations in PTEN-induced putative kinase 1 associated with ... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:20798600 The PINK1/Parkin-mediated mitophagy is compromised by PD-ass... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:23885119 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized m... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IGI PMID:21355049 Functional alteration of PARL contributes to mitochondrial d... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005739 mitochondrion | IMP PMID:24184327 Mitochondrial impairment increases FL-PINK1 levels by calciu... | ACCEPT | Summary: PINK1 is a mitochondrially targeted kinase. Reason: Correct; GO:0005741 is the more informative location. Supporting Evidence: PMID:15087508 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. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:15087508 Hereditary early-onset Parkinson's disease caused by mutatio... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:16672980 Mitochondrial dysfunction in Drosophila PINK1 mutants is com... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:20798600 The PINK1/Parkin-mediated mitophagy is compromised by PD-ass... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:18687899 The kinase domain of mitochondrial PINK1 faces the cytoplasm... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:21426348 The mitochondrial intramembrane protease PARL cleaves human ... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | IMP PMID:25527497 PINK1 kinase catalytic activity is regulated by phosphorylat... | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5205672 | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9834076 | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9834945 | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9835011 | ACCEPT | Summary: On depolarized mitochondria, PINK1 import is blocked and full-length PINK1 accumulates at the TOM complex on the outer membrane, with its kinase domain facing the cytosol. Reason: Core functional location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:17579517 PINK1 protects against oxidative stress by phosphorylating m... | KEEP AS NON CORE | Summary: In healthy, polarized mitochondria the PINK1 precursor is imported through TOM/TIM23 and its TM segment is cleaved by PARL in the inner membrane. Reason: PINK1 transiently resides in the inner membrane during import and processing, but the location where it acts (as a kinase) is the outer membrane of damaged mitochondria. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. PMID:21426348 Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:21426348 The mitochondrial intramembrane protease PARL cleaves human ... | KEEP AS NON CORE | Summary: In healthy, polarized mitochondria the PINK1 precursor is imported through TOM/TIM23 and its TM segment is cleaved by PARL in the inner membrane. Reason: PINK1 transiently resides in the inner membrane during import and processing, but the location where it acts (as a kinase) is the outer membrane of damaged mitochondria. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. PMID:21426348 Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: In healthy, polarized mitochondria the PINK1 precursor is imported through TOM/TIM23 and its TM segment is cleaved by PARL in the inner membrane. Reason: PINK1 transiently resides in the inner membrane during import and processing, but the location where it acts (as a kinase) is the outer membrane of damaged mitochondria. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. PMID:21426348 Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In healthy, polarized mitochondria the PINK1 precursor is imported through TOM/TIM23 and its TM segment is cleaved by PARL in the inner membrane. Reason: PINK1 transiently resides in the inner membrane during import and processing, but the location where it acts (as a kinase) is the outer membrane of damaged mitochondria. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. PMID:21426348 Upon depolarization of the mitochondrial membrane potential, the canonical import of Pink1 and PARL-catalyzed processing is blocked, leading to accumulation of the Pink1 precursor. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:17579517 PINK1 protects against oxidative stress by phosphorylating m... | KEEP AS NON CORE | Summary: PARL-processed PINK1 can be released into the intermembrane space or cytosol. Reason: Transit/processing location; non-core. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:21426348 The mitochondrial intramembrane protease PARL cleaves human ... | KEEP AS NON CORE | Summary: PARL-processed PINK1 can be released into the intermembrane space or cytosol. Reason: Transit/processing location; non-core. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-5205661 | KEEP AS NON CORE | Summary: PARL-processed PINK1 can be released into the intermembrane space or cytosol. Reason: Transit/processing location; non-core. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-5205672 | KEEP AS NON CORE | Summary: PARL-processed PINK1 can be released into the intermembrane space or cytosol. Reason: Transit/processing location; non-core. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-5205681 | KEEP AS NON CORE | Summary: PARL-processed PINK1 can be released into the intermembrane space or cytosol. Reason: Transit/processing location; non-core. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005783 endoplasmic reticulum | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | KEEP AS NON CORE | Summary: Endogenous PINK1 immunoprecipitated from marker-controlled ER fractions of NTera2-derived human cells and mouse brain, where it binds NENF (PMID:31536960). A minor ER-associated pool; PINK1 acts on the mitochondrial outer membrane. Reason: Minor location; not where PINK1 performs its core function. ORGANELLES check (2026-11-05): the assay is subcellular fractionation with mitochondrial, ER and MAM markers as internal controls, then immunoprecipitation of the endogenous protein, so an ER-fraction pool is shown, but the assay cannot resolve membrane from lumen and does not show kinase activity at the ER. PINK1 carries a mitochondrial transit peptide and no ER-targeting signal, so the pool is most likely cytosolic PINK1 (for example the PARL-processed form) or PINK1 at ER-mitochondria contacts; it stays at the root. The human UniProt entry no longer lists the ER (its curated locations are mitochondrial membranes and cytosol), so this IDA is the only ER evidence; MARK_AS_OVER_ANNOTATED would be the alternative if the single co-fractionation result is judged too thin. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain using anti-PINK1 and DJ-1 antibodies immunoblotted (IB) with anti-NENF antibody (i). mt, ER, and MAM markers (ii) used as internal control. PMID:31536960 Similarly, NENF was found to interact with a PD-contributing protein, PINK1 (PTEN-induced putative kinase 1; Figure 6B) |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined electronic annotation (GO_REF:0000120) whose sources are an ARBA rule (ARBA00028672) and the mouse and rat orthologs; neither the human, mouse (Q99MQ3) nor rat (B5DFG1) UniProt entry now lists an ER location, so the row rests on the ARBA prediction. The ER claim itself is supported only by the human IDA (PMID:31536960). Reason: Minor location; not where PINK1 performs its core function. ORGANELLES check (2026-11-05): the electronic source is an unvetted ARBA association rule rather than a curated ortholog location (Q99MQ3 and B5DFG1 list mitochondrial outer and inner membrane and cytosol only), so on its own this row would be MARK_AS_OVER_ANNOTATED. It is kept as non-core only because the claim it makes matches the human IDA row, which recovers endogenous PINK1 from a marker-controlled ER fraction; both rows carry the same action. No sub-compartment: PINK1 has a mitochondrial transit peptide and no ER-targeting signal. Supporting Evidence: PMID:31536960 PINK1 and DJ-1 immunoprecipitates in whole-cell extract (WCE) as well as in mt, ER, and MAM lysates from ECSCs, DNLCs, and mouse brain using anti-PINK1 and DJ-1 antibodies immunoblotted (IB) with anti-NENF antibody (i). mt, ER, and MAM markers (ii) used as internal control. PMID:31536960 Similarly, NENF was found to interact with a PD-contributing protein, PINK1 (PTEN-induced putative kinase 1; Figure 6B) |
| GO:0005829 cytosol | IDA PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:20798600 The PINK1/Parkin-mediated mitophagy is compromised by PD-ass... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:21426348 The mitochondrial intramembrane protease PARL cleaves human ... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IDA PMID:24798695 PARK13 regulates PINK1 and subcellular relocation patterns u... | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5205661 | ACCEPT | Summary: After PARL cleavage in healthy mitochondria, the 52 kDa PINK1 fragment is released to the cytosol, where it is degraded by the proteasome and can bind Parkin. Reason: Well documented location of the processed PINK1 pool. Precursor PINK1 also transits the cytosol before import. Supporting Evidence: PMID:21426348 Here, we show that PARL cleaves human Pink1, which is implicated in Parkinson's disease, within its conserved membrane anchor. Mature Pink1 is then free to be released into the cytosol or the mitochondrial intermembrane space. |
| GO:0005856 cytoskeleton | IDA PMID:24798695 PARK13 regulates PINK1 and subcellular relocation patterns u... | KEEP AS NON CORE | Summary: Reported cytoskeletal localization of PINK1 in neuronal cells (single study). Reason: Unusual, non-core location. Supporting Evidence: PMID:24798695 We show that PARK13 localizes to a variety of subcellular locations in neuronal cells and that PINK1, although more restrictive, also localizes to locations other than those previously reported. |
| GO:0006468 protein phosphorylation | IDA PMID:14607334 BRPK, a novel protein kinase showing increased expression in... | ACCEPT | Summary: PINK1 phosphorylates ubiquitin, Parkin, Miro, DRP1 and itself. Reason: Core. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:25527291 Here, we show that PINK1 can phosphorylate every Ub in Ub chains. PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. |
| GO:0006468 protein phosphorylation | IDA PMID:25527291 Ubiquitin Ser65 phosphorylation affects ubiquitin structure,... | ACCEPT | Summary: PINK1 phosphorylates ubiquitin, Parkin, Miro, DRP1 and itself. Reason: Core. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:25527291 Here, we show that PINK1 can phosphorylate every Ub in Ub chains. PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. |
| GO:0006468 protein phosphorylation | IDA PMID:32139798 The mitochondrial inner membrane protein LETM1 modulates cri... | ACCEPT | Summary: PINK1 phosphorylates ubiquitin, Parkin, Miro, DRP1 and itself. Reason: Core. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:25527291 Here, we show that PINK1 can phosphorylate every Ub in Ub chains. PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. |
| GO:0006468 protein phosphorylation | IMP PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: PINK1 phosphorylates ubiquitin, Parkin, Miro, DRP1 and itself. Reason: Core. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:25527291 Here, we show that PINK1 can phosphorylate every Ub in Ub chains. PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. |
| GO:0006511 ubiquitin-dependent protein catabolic process | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | MARK AS OVER ANNOTATED | Summary: Review statement linking PINK1 to ubiquitin-dependent catabolism. Reason: PINK1 promotes ubiquitin-dependent mitophagy and is itself degraded by the proteasome, but it is not a component of the ubiquitin-dependent protein catabolic machinery. Supporting Evidence: PMID:24522549 PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very broad electronic term. Reason: Broad but not incorrect; uninformative. |
| GO:0006979 response to oxidative stress | IGI PMID:24475098 BAG5 protects against mitochondrial oxidative damage through... | KEEP AS NON CORE | Summary: PINK1 stability (regulated by BAG5) affects mitochondrial oxidative damage. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:24475098 Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. |
| GO:0007005 mitochondrion organization | IMP PMID:18560593 PINK1 is necessary for long term survival and mitochondrial ... | KEEP AS NON CORE | Summary: PINK1 deficiency causes mitochondrial dysfunction and morphology defects in human neurons. Reason: Broad term; the specific roles are mitophagy and regulation of fission/transport. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0009966 regulation of signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very broad electronic term. Reason: Broad but not incorrect; uninformative. |
| GO:0010310 regulation of hydrogen peroxide metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred regulation of H2O2 metabolism. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic gene-expression regulation transferred from orthologs or inferred from BAG5-PINK1 data. Reason: Too unspecific and indirect; PINK1 is a kinase without a direct gene-regulatory role. Supporting Evidence: PMID:24475098 Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. |
| GO:0010629 negative regulation of gene expression | ISS PMID:24475098 BAG5 protects against mitochondrial oxidative damage through... | MARK AS OVER ANNOTATED | Summary: Generic gene-expression regulation transferred from orthologs or inferred from BAG5-PINK1 data. Reason: Too unspecific and indirect; PINK1 is a kinase without a direct gene-regulatory role. Supporting Evidence: PMID:24475098 Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. |
| GO:0010821 regulation of mitochondrion organization | IMP PMID:21508222 Mitochondrial Parkin recruitment is impaired in neurons deri... | KEEP AS NON CORE | Summary: PINK1 mutant iPSC-derived neurons show altered mitochondrial recruitment of Parkin and copy number. Reason: Broad term; the core role is mitophagy initiation. Supporting Evidence: PMID:21508222 These cells were differentiated into dopaminergic neurons that upon mitochondrial depolarization showed impaired recruitment of lentivirally expressed Parkin to mitochondria |
| GO:0016020 membrane | IDA PMID:24798695 PARK13 regulates PINK1 and subcellular relocation patterns u... | ACCEPT | Summary: PINK1 is a membrane-anchored protein (single TM segment in the mitochondrial membranes). Reason: Correct, broad location. Supporting Evidence: PMID:18687899 We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. |
| GO:0016236 macroautophagy | TAS Reactome:R-HSA-5205685 | ACCEPT | Summary: PINK1/Parkin mitophagy is a form of selective macroautophagy. Reason: Correct parent of the core process. Supporting Evidence: PMID:20871098 Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | ACCEPT | Summary: PINK1 is required for CCCP-induced mitophagy, a selective macroautophagy. Reason: Supported by IMP data. Supporting Evidence: PMID:20871098 Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. |
| GO:0016242 negative regulation of macroautophagy | IMP PMID:19279012 Loss of PINK1 function promotes mitophagy through effects on... | MARK AS OVER ANNOTATED | Summary: Knockdown of PINK1 in SH-SY5Y cells increased autophagy, attributed to oxidative stress. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:19279012 We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. |
| GO:0016301 kinase activity | IDA PMID:15824318 Mutations in PTEN-induced putative kinase 1 associated with ... | MODIFY | Summary: PINK1 is a protein kinase. Kinase activity was confirmed in vitro and abolished by kinase-dead mutations. Reason: Correct but too general; PINK1 is specifically a protein Ser/Thr kinase. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0016301 kinase activity | IEA GO_REF:0000107 | MODIFY | Summary: PINK1 is a protein kinase. Kinase activity was confirmed in vitro and abolished by kinase-dead mutations. Reason: Correct but too general; PINK1 is specifically a protein Ser/Thr kinase. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0016301 kinase activity | NAS PMID:21563316 Synaptic vesicle trafficking and Parkinson's disease. | MODIFY | Summary: PINK1 is a protein kinase. Kinase activity was confirmed in vitro and abolished by kinase-dead mutations. Reason: Correct but too general; PINK1 is specifically a protein Ser/Thr kinase. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:15824318 We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. |
| GO:0016504 peptidase activator activity | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | MARK AS OVER ANNOTATED | Summary: A review states that PINK1 stimulates HtrA2/Omi protease activity. Reason: PINK1 is a kinase, not a peptidase activator by binding. Any effect on HtrA2 is indirect (proposed phosphorylation-dependent), and this TAS from a review is not direct evidence for the MF. Supporting Evidence: PMID:24522549 PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. |
| GO:0016567 protein ubiquitination | IMP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | MODIFY | Summary: PINK1 is required for Parkin/Fbxo7-dependent ubiquitination of mitofusins and mitophagy. Reason: PINK1 is not the E3 ligase. It drives ubiquitination by phosphorylating ubiquitin and Parkin, which makes it a positive regulator. Proposed replacements: positive regulation of protein ubiquitination Supporting Evidence: PMID:23933751 Thus, even though overexpression of human Fbxo7 can suppress parkin mutants, Fbxo7 requires PINK1 activity for its protective function consistent with the data showing Fbxo7 requires PINK1 for its translocation to the mitochondria. PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. |
| GO:0019900 kinase binding | IPI PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: PINK1 associates with kinases (e.g. mTORC2/AKT pathway components). Reason: A binding term that adds little; non-core. Supporting Evidence: PMID:21177249 Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. |
| GO:0022904 respiratory electron transport chain | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred respiratory electron transport chain. Reason: PINK1 is not an electron transport chain component; effects on respiration are regulatory or indirect. |
| GO:0030097 hemopoiesis | IGI PMID:33406421 OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-... | KEEP AS NON CORE | Summary: In mouse HSCs, OGT maintains Pink1 expression and PINK1-dependent mitophagy, which is required for HSC maintenance. Reason: A tissue-level consequence of PINK1-dependent mitophagy; not a core function. Supporting Evidence: PMID:33406421 Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. |
| GO:0030335 positive regulation of cell migration | IMP PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: Reported effect of PINK1/AKT signalling on cell migration. Reason: Single-study, peripheral observation. Supporting Evidence: PMID:21177249 Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. |
| GO:0030424 axon | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | KEEP AS NON CORE | Summary: PINK1 detected in axons in human brain. Reason: Neuronal compartment location (reflects mitochondria in axons); non-core. Supporting Evidence: PMID:16702191 In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. |
| GO:0030426 growth cone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred growth cone localization (neuronal mitochondria). Reason: Non-core neuronal compartment. |
| GO:0031396 regulation of protein ubiquitination | IDA PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | ACCEPT | Summary: PINK1 regulates Parkin E3 activity and Parkin-mediated ubiquitination through Ser65 phosphorylation. Reason: Core regulatory role. Supporting Evidence: PMID:19880420 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. PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. |
| GO:0031396 regulation of protein ubiquitination | IMP PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | ACCEPT | Summary: PINK1 regulates Parkin E3 activity and Parkin-mediated ubiquitination through Ser65 phosphorylation. Reason: Core regulatory role. Supporting Evidence: PMID:19880420 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. PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. |
| GO:0031396 regulation of protein ubiquitination | IMP PMID:23212910 Phosphatase and tensin homolog (PTEN)-induced putative kinas... | ACCEPT | Summary: PINK1 regulates Parkin E3 activity and Parkin-mediated ubiquitination through Ser65 phosphorylation. Reason: Core regulatory role. Supporting Evidence: PMID:19880420 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. PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. |
| GO:0031398 positive regulation of protein ubiquitination | ISS GO_REF:0000024 | ACCEPT | Summary: PINK1 activates Parkin-mediated ubiquitination of mitochondrial outer-membrane proteins by phosphorylating ubiquitin and Parkin. Reason: Core regulatory role. Supporting Evidence: PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. PMID:19880420 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. |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PINK1 binds the E3 ligase Parkin; PD-linked PINK1 mutations reduce this binding. Reason: Binding is real and functionally relevant, but the informative activity is PINK1 phosphorylating Parkin and ubiquitin. Supporting Evidence: PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:20798600 The PINK1/Parkin-mediated mitophagy is compromised by PD-ass... | KEEP AS NON CORE | Summary: PINK1 binds the E3 ligase Parkin; PD-linked PINK1 mutations reduce this binding. Reason: Binding is real and functionally relevant, but the informative activity is PINK1 phosphorylating Parkin and ubiquitin. Supporting Evidence: PMID:20798600 Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PINK1 protects cells against oxidative stress, and PINK1-mutant neural cells show mitochondrial vulnerability to stress. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. PMID:24522549 PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. |
| GO:0034599 cellular response to oxidative stress | IMP PMID:22764206 Pharmacological rescue of mitochondrial deficits in iPSC-der... | KEEP AS NON CORE | Summary: PINK1 protects cells against oxidative stress, and PINK1-mutant neural cells show mitochondrial vulnerability to stress. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. PMID:24522549 PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. |
| GO:0034599 cellular response to oxidative stress | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | KEEP AS NON CORE | Summary: PINK1 protects cells against oxidative stress, and PINK1-mutant neural cells show mitochondrial vulnerability to stress. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. PMID:24522549 PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. |
| GO:0035556 intracellular signal transduction | IDA PMID:14607334 BRPK, a novel protein kinase showing increased expression in... | MARK AS OVER ANNOTATED | Summary: Very general signalling term. The original BRPK paper only characterized the kinase and its autophosphorylation. Reason: Too unspecific to be informative. PINK1 signalling is better captured by its kinase activity and roles in mitophagy and Parkin activation. Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Very general signalling term. The original BRPK paper only characterized the kinase and its autophosphorylation. Reason: Too unspecific to be informative. PINK1 signalling is better captured by its kinase activity and roles in mitophagy and Parkin activation. Supporting Evidence: PMID:14607334 BRPK has a serine/threonine-type protein kinase domain, and the recombinant proteins of BRPK were capable of autophosphorylation. |
| GO:0038203 TORC2 signaling | IDA PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: Overexpressed PINK1 was reported to activate mTORC2 (Rictor phosphorylation), leading to AKT Ser473 phosphorylation and cytoprotection. Reason: Single-group report of a cytosolic PINK1 signalling pathway. Plausible but not part of the established core mechanism. Supporting Evidence: PMID:21177249 Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. |
| GO:0042981 regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PINK1 regulates apoptosis in many systems. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PINK1 is anti-apoptotic in many cell models. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | KEEP AS NON CORE | Summary: PINK1 phosphorylation of Parkin enhances Parkin-mediated K63 ubiquitin signalling to IKK/NF-kappaB. Reason: Experimental but peripheral to the core mitophagy function. Supporting Evidence: PMID:19880420 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. |
| GO:0043254 regulation of protein-containing complex assembly | IDA PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | KEEP AS NON CORE | Summary: PINK1 phosphorylation of Parkin enhances Parkin-mediated ubiquitin signalling complexes. Reason: Non-core. Supporting Evidence: PMID:19880420 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. |
| GO:0043422 protein kinase B binding | IDA PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: PINK1 was reported to associate with AKT signalling. Reason: Single-study binding; non-core. Supporting Evidence: PMID:21177249 Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. |
| GO:0043523 regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred regulation of neuron apoptosis. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0043524 negative regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PINK1 deficiency reduces long-term viability of human neurons. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:18560593 PINK1 is necessary for long term survival and mitochondrial ... | KEEP AS NON CORE | Summary: PINK1 deficiency reduces long-term viability of human neurons. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0044297 cell body | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | KEEP AS NON CORE | Summary: PINK1 detected in neuronal cell bodies in human brain. Reason: Cellular compartment location; non-core. Supporting Evidence: PMID:16702191 In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. |
| GO:0044877 protein-containing complex binding | IMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of... | KEEP AS NON CORE | Summary: Uninformative binding term from an RNAi screen for regulators of Parkin translocation. Reason: The row is a mutant-phenotype annotation from genome-wide RNAi screens for regulators of Parkin recruitment, of which only the abstract is available, and this review itself records that PINK1 associates with the TOM complex of the mitochondrial outer membrane. Binding of a protein complex by PINK1 is therefore not in dispute, and an uninformative term is not a ground for removing a true experimental annotation. Association with the import machinery is how PINK1 is stabilized on damaged mitochondria rather than its kinase function, so the row is kept as non-core. |
| GO:0045727 positive regulation of translation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred positive regulation of translation (e.g. from studies of PINK1 effects on local or IRES-dependent translation). Reason: Ortholog-transferred (Ensembl Compara) annotation, most likely from a rodent phenotype or expression study. PINK1 loss causes broad mitochondrial dysfunction, so many stress and physiological readouts change secondarily. That does not show PINK1 performs a step of this process. Supporting Evidence: PMID:24553947 PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1Ξ± protein, HIF-1Ξ± transcriptional activity, and hypoxia-responsive gene upregulation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred positive regulation of transcription. Reason: PINK1 is a mitochondrial kinase with no direct transcriptional role. Ortholog-transferred (Ensembl Compara) annotation, most likely from a rodent phenotype or expression study. PINK1 loss causes broad mitochondrial dysfunction, so many stress and physiological readouts change secondarily. That does not show PINK1 performs a step of this process. |
| GO:0046329 negative regulation of JNK cascade | TAS PMID:18221368 Biochemical aspects of the neuroprotective mechanism of PTEN... | MARK AS OVER ANNOTATED | Summary: Review-based statement about PINK1 neuroprotective signalling. Reason: Not supported by direct evidence that PINK1 controls JNK signalling. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | KEEP AS NON CORE | Summary: PINK1 detected in the perinuclear region in brain tissue. Reason: Reflects perinuclear clustering of mitochondria; non-core. Supporting Evidence: PMID:16702191 In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. |
| GO:0050821 protein stabilization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Reported effects of PINK1 on the levels of its partners within a PINK1-Parkin-DJ-1 complex, and orthology transfer. Reason: An indirect effect on protein levels; not a defined PINK1 activity. |
| GO:0050821 protein stabilization | IMP PMID:19229105 Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex p... | MARK AS OVER ANNOTATED | Summary: Reported effects of PINK1 on the levels of its partners within a PINK1-Parkin-DJ-1 complex, and orthology transfer. Reason: An indirect effect on protein levels; not a defined PINK1 activity. |
| GO:0051049 regulation of transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very broad electronic term (e.g. reflecting PINK1 arrest of mitochondrial transport through Miro). Reason: Broad; the specific role is arrest of mitochondrial movement via Miro phosphorylation. Supporting Evidence: PMID:22078885 PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. |
| GO:0051246 regulation of protein metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very broad electronic term. Reason: Broad but not incorrect; uninformative. |
| GO:0051881 regulation of mitochondrial membrane potential | IGI PMID:24475098 BAG5 protects against mitochondrial oxidative damage through... | KEEP AS NON CORE | Summary: PINK1 loss reduces mitochondrial membrane potential. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0051881 regulation of mitochondrial membrane potential | IMP PMID:18560593 PINK1 is necessary for long term survival and mitochondrial ... | KEEP AS NON CORE | Summary: PINK1 loss reduces mitochondrial membrane potential. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0051881 regulation of mitochondrial membrane potential | IMP PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | KEEP AS NON CORE | Summary: PINK1 loss reduces mitochondrial membrane potential. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: PINK1 overexpression enhanced AKT Ser473 phosphorylation via mTORC2, not PI3K. Reason: The paper states activation was not through PI3K, so the PI3K/AKT term is only partly apt. Non-core. Supporting Evidence: PMID:21177249 Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. |
| GO:0055131 C3HC4-type RING finger domain binding | IPI PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | KEEP AS NON CORE | Summary: PINK1 interacts with Parkin, including its RING-containing region, as part of PINK1-Parkin signalling. Reason: A domain-specific binding term that reflects the PINK1-Parkin interaction. The functionally meaningful activity is PINK1 phosphorylating Parkin (Ser65 of the Ubl) and ubiquitin. Supporting Evidence: PMID:19880420 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. |
| GO:0061136 regulation of proteasomal protein catabolic process | NAS PMID:22078885 PINK1 and Parkin target Miro for phosphorylation and degrada... | KEEP AS NON CORE | Summary: PINK1 phosphorylation of Miro triggers Parkin-dependent proteasomal degradation of Miro. Reason: Mechanistically specific, but secondary to the core role. Supporting Evidence: PMID:22078885 PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. PMID:22078885 The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. |
| GO:0070585 protein localization to mitochondrion | IMP PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: PINK1 controls the localization of Parkin to mitochondria in a kinase-dependent manner. Reason: Core process role: PINK1 recruits Parkin to damaged mitochondria. Supporting Evidence: PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. PMID:20798600 PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. |
| GO:0070585 protein localization to mitochondrion | IMP PMID:25527497 PINK1 kinase catalytic activity is regulated by phosphorylat... | ACCEPT | Summary: PINK1 controls the localization of Parkin to mitochondria in a kinase-dependent manner. Reason: Core process role: PINK1 recruits Parkin to damaged mitochondria. Supporting Evidence: PMID:18957282 PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. PMID:20798600 PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PINK1-null mouse cells show reduced hypoxic induction of HIF-1alpha through effects on 4E-BP1-dependent translation. Reason: Experimental but peripheral to the core mitophagy function. Supporting Evidence: PMID:24553947 PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1Ξ± protein, HIF-1Ξ± transcriptional activity, and hypoxia-responsive gene upregulation |
| GO:0071456 cellular response to hypoxia | IMP PMID:24553947 Loss of PINK1 attenuates HIF-1Ξ± induction by preventing 4E-B... | KEEP AS NON CORE | Summary: PINK1-null mouse cells show reduced hypoxic induction of HIF-1alpha through effects on 4E-BP1-dependent translation. Reason: Experimental but peripheral to the core mitophagy function. Supporting Evidence: PMID:24553947 PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1Ξ± protein, HIF-1Ξ± transcriptional activity, and hypoxia-responsive gene upregulation |
| GO:0072656 maintenance of protein location in mitochondrion | IMP PMID:25527497 PINK1 kinase catalytic activity is regulated by phosphorylat... | KEEP AS NON CORE | Summary: PINK1 autophosphorylation sites (Ser228/Ser402) regulate its activity and its retention/function on mitochondria. Reason: Experimental, mechanistic; non-core. Supporting Evidence: PMID:25527497 Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. |
| GO:0090141 positive regulation of mitochondrial fission | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PINK1 directly phosphorylates DRP1 at Ser616 to promote mitophagy-independent fission, and PINK1 promotes fission in Drosophila. Reason: Supported (IBA plus direct biochemistry) but secondary to the core mitophagy-initiation function. Supporting Evidence: PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. PMID:32484300 PINK1-mediated mitochondrial fission is Drp1S616 phosphorylation dependent. |
| GO:0090141 positive regulation of mitochondrial fission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PINK1 directly phosphorylates DRP1 at Ser616 to promote mitophagy-independent fission, and PINK1 promotes fission in Drosophila. Reason: Supported (IBA plus direct biochemistry) but secondary to the core mitophagy-initiation function. Supporting Evidence: PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. PMID:32484300 PINK1-mediated mitochondrial fission is Drp1S616 phosphorylation dependent. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | IMP PMID:19880420 Phosphorylation of parkin by Parkinson disease-linked kinase... | MODIFY | Summary: In the cited study, depletion of endogenous PINK1 enhanced rotenone-induced cytochrome c release, so PINK1 restrains cytochrome c release. Reason: The cited paper shows the opposite direction to the annotated term. The supported annotation is negative regulation of release of cytochrome c (non-core). Proposed replacements: negative regulation of release of cytochrome c from mitochondria Supporting Evidence: PMID:19880420 Analyses of cell viability and cytochrome c release revealed that siRNA-mediated depletion of endogenous PINK1 significantly enhanced the susceptibility of SH-SY5Y cells to rotenone-induced cytochrome c release PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. |
| GO:0090258 negative regulation of mitochondrial fission | IMP PMID:19279012 Loss of PINK1 function promotes mitophagy through effects on... | MARK AS OVER ANNOTATED | Summary: PINK1 knockdown in SH-SY5Y cells caused mitochondrial fragmentation. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Other studies show PINK1 directly promotes fission by phosphorylating DRP1 Ser616. Supporting Evidence: PMID:19279012 We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0097237 cellular response to toxic substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: PINK1 loss sensitizes cells to toxins (e.g. MPP+, rotenone). Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. |
| GO:0097237 cellular response to toxic substance | TAS PMID:18221368 Biochemical aspects of the neuroprotective mechanism of PTEN... | MARK AS OVER ANNOTATED | Summary: PINK1 loss sensitizes cells to toxins (e.g. MPP+, rotenone). Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. |
| GO:0097413 Lewy body | TAS PMID:24522549 Oxidative stress-induced signaling pathways implicated in th... | KEEP AS NON CORE | Summary: PINK1 immunoreactivity has been detected in Lewy bodies in Parkinson disease brain. Reason: Pathological inclusion localization; not a site of normal PINK1 function. Supporting Evidence: PMID:16702191 In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. |
| GO:0097449 astrocyte projection | IDA PMID:16702191 PINK1 protein in normal human brain and Parkinson's disease. | KEEP AS NON CORE | Summary: PINK1 immunoreactivity was detected in astrocytic processes in human brain. Reason: Cell-type-specific location (reflects mitochondria in these compartments); not informative about core function. Supporting Evidence: PMID:16702191 In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. |
| GO:0099074 mitochondrion to lysosome vesicle-mediated transport | IMP PMID:24446486 Parkin and PINK1 function in a vesicular trafficking pathway... | KEEP AS NON CORE | Summary: PINK1 is required for a Parkin-dependent mitochondria-derived vesicle (MDV) pathway that delivers oxidized cargo to lysosomes. Reason: Experimentally supported, distinct quality-control pathway; less established than mitophagy. Supporting Evidence: PMID:24446486 These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. |
| GO:0106310 protein serine kinase activity | EXP PMID:18957282 PINK1 controls mitochondrial localization of Parkin through ... | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0106310 protein serine kinase activity | EXP PMID:24660806 Parkin is activated by PINK1-dependent phosphorylation of ub... | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0106310 protein serine kinase activity | EXP PMID:24751536 PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquit... | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0106310 protein serine kinase activity | EXP PMID:24784582 Ubiquitin is phosphorylated by PINK1 to activate parkin. | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:0106310 protein serine kinase activity | IMP PMID:32484300 PINK1 phosphorylates Drp1(S616) to regulate mitophagy-indepe... | ACCEPT | Summary: PINK1 phosphorylates Ser65 of ubiquitin and of the Parkin Ubl domain, and Ser616 of DRP1. Reason: Core MF; directly shown in several studies. Supporting Evidence: PMID:24751536 Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. PMID:24660806 Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. PMID:32484300 We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. |
| GO:1900407 regulation of cellular response to oxidative stress | IMP PMID:24446486 Parkin and PINK1 function in a vesicular trafficking pathway... | KEEP AS NON CORE | Summary: PINK1 is required for the MDV pathway that removes oxidized mitochondrial cargo in response to oxidative stress. Reason: Non-core. Supporting Evidence: PMID:24446486 These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. |
| GO:1901525 negative regulation of mitophagy | IMP PMID:19279012 Loss of PINK1 function promotes mitophagy through effects on... | MARK AS OVER ANNOTATED | Summary: PINK1 knockdown increased mitophagy in SH-SY5Y cells (secondary to oxidative stress). Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. In the canonical pathway PINK1 is required for, not inhibitory to, damage-induced mitophagy. Supporting Evidence: PMID:19279012 We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. PMID:20871098 Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. |
| GO:1902803 regulation of synaptic vesicle transport | TAS PMID:21563316 Synaptic vesicle trafficking and Parkinson's disease. | MARK AS OVER ANNOTATED | Summary: A review speculating on roles of PD genes in synaptic vesicle cycling. Reason: Speculative review statement, not direct evidence of PINK1 controlling synaptic vesicle transport. Supporting Evidence: PMID:21563316 This article reviews our current understanding for a role of causative PD genes in the SV cycle and speculates on the potential role of aberrant SV trafficking in the neurodegenerative cascade of PD. |
| GO:1902902 negative regulation of autophagosome assembly | IMP PMID:19279012 Loss of PINK1 function promotes mitophagy through effects on... | MARK AS OVER ANNOTATED | Summary: Knockdown of PINK1 in SH-SY5Y cells increased autophagy and mitochondrial fragmentation, attributed to oxidative stress. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. PINK1 is a positive driver of mitophagy in the canonical pathway. Supporting Evidence: PMID:19279012 We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. |
| GO:1902958 positive regulation of mitochondrial electron transport, NADH to ubiquinone | TAS PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | KEEP AS NON CORE | Summary: PINK1 has been linked to complex I activity (e.g. via NDUFA10 phosphorylation); the cited study concerns PARL processing of PINK1 and mitochondrial phenotypes. Reason: Peripheral, secondary role. Supporting Evidence: PMID:21138942 Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) |
| GO:1903146 regulation of autophagy of mitochondrion | TAS PMID:21563316 Synaptic vesicle trafficking and Parkinson's disease. | ACCEPT | Summary: PINK1 regulates mitochondrial autophagy as its upstream kinase. Reason: Consistent with the core role (review statement). Supporting Evidence: PMID:21563316 This article reviews our current understanding for a role of causative PD genes in the SV cycle and speculates on the potential role of aberrant SV trafficking in the neurodegenerative cascade of PD. |
| GO:1903298 negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred protection from hypoxia-induced intrinsic apoptosis. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IDA PMID:16632486 Association of PINK1 and DJ-1 confers digenic inheritance of... | KEEP AS NON CORE | Summary: Co-expression of DJ-1 and PINK1 protects dopaminergic SH-SY5Y cells from MPP+-induced death. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:16632486 co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP(+))-induced death of dopaminergic SH-SY5Y cells |
| GO:1903384 negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway | IDA PMID:21177249 A new cytosolic pathway from a Parkinson disease-associated ... | KEEP AS NON CORE | Summary: PINK1 protects neurons/neuroblastoma cells against H2O2-induced death, and the P209A PD mutation enhances H2O2-induced death and caspase-3 activation. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:23261939 The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. PMID:21177249 Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. |
| GO:1903384 negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway | IMP PMID:23261939 Increase of oxidative stress by a novel PINK1 mutation, P209... | KEEP AS NON CORE | Summary: PINK1 protects neurons/neuroblastoma cells against H2O2-induced death, and the P209A PD mutation enhances H2O2-induced death and caspase-3 activation. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:23261939 The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. PMID:21177249 Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. |
| GO:1903747 obsolete regulation of protein localization to mitochondrion | IGI PMID:21508222 Mitochondrial Parkin recruitment is impaired in neurons deri... | MODIFY | Summary: Patient-derived PINK1-mutant neurons and fibroblasts show impaired Parkin recruitment to depolarized mitochondria. Reason: GOA labels this term obsolete. The PINK1-dependent recruitment of Parkin to mitochondria is captured by protein localization to mitochondrion. Proposed replacements: protein localization to mitochondrion Supporting Evidence: PMID:21508222 These cells were differentiated into dopaminergic neurons that upon mitochondrial depolarization showed impaired recruitment of lentivirally expressed Parkin to mitochondria PMID:20798600 PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. |
| GO:1903747 obsolete regulation of protein localization to mitochondrion | IMP PMID:23212910 Phosphatase and tensin homolog (PTEN)-induced putative kinas... | MODIFY | Summary: Patient-derived PINK1-mutant neurons and fibroblasts show impaired Parkin recruitment to depolarized mitochondria. Reason: GOA labels this term obsolete. The PINK1-dependent recruitment of Parkin to mitochondria is captured by protein localization to mitochondrion. Proposed replacements: protein localization to mitochondrion Supporting Evidence: PMID:21508222 These cells were differentiated into dopaminergic neurons that upon mitochondrial depolarization showed impaired recruitment of lentivirally expressed Parkin to mitochondria PMID:20798600 PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. |
| GO:1903749 obsolete positive regulation of protein localization to mitochondrion | HMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of... | MODIFY | Summary: PINK1 is required for, and promotes, recruitment of Parkin from the cytosol to damaged mitochondria (identified in a genome-wide RNAi screen for regulators of Parkin translocation). Reason: GOA labels this term obsolete. The biology (PINK1-dependent localization of Parkin to mitochondria) is real and core, and it is represented by protein localization to mitochondrion, which PINK1 already carries by IMP. Proposed replacements: protein localization to mitochondrion Supporting Evidence: PMID:22354088 However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. PMID:20798600 PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. |
| GO:1903751 negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide | IDA PMID:17579517 PINK1 protects against oxidative stress by phosphorylating m... | KEEP AS NON CORE | Summary: PINK1 suppresses oxidative-stress-induced cytochrome c release and cell death through phosphorylation of TRAP1. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:17579517 We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. |
| GO:1903852 positive regulation of cristae formation | IMP PMID:19279012 Loss of PINK1 function promotes mitophagy through effects on... | MARK AS OVER ANNOTATED | Summary: Altered cristae after PINK1 knockdown. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:19279012 We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. |
| GO:1904544 positive regulation of free ubiquitin chain polymerization | ISS GO_REF:0000024 | ACCEPT | Summary: By phosphorylating ubiquitin and the Parkin Ubl at Ser65, PINK1 activates Parkin E3 activity, including free ubiquitin-chain synthesis. Reason: Directly follows from PINK1 activating Parkin; consistent with biochemistry. Supporting Evidence: PMID:24751536 Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. PMID:24660806 stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain |
| GO:1904881 cellular response to hydrogen sulfide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred response to hydrogen sulfide. Reason: Ortholog-transferred (Ensembl Compara) annotation, most likely from a rodent phenotype or expression study. PINK1 loss causes broad mitochondrial dysfunction, so many stress and physiological readouts change secondarily. That does not show PINK1 performs a step of this process. |
| GO:1905091 positive regulation of type 2 mitophagy | IMP PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | ACCEPT | Summary: PINK1 is required for depolarization-induced (type 2) mitophagy, which it initiates by activating Parkin. Reason: Core. Supporting Evidence: PMID:20871098 Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. |
| GO:2000377 regulation of reactive oxygen species metabolic process | IGI PMID:24475098 BAG5 protects against mitochondrial oxidative damage through... | KEEP AS NON CORE | Summary: PINK1 loss increases ROS levels. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:23261939 The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. |
| GO:2000377 regulation of reactive oxygen species metabolic process | IMP PMID:21138942 PINK1 cleavage at position A103 by the mitochondrial proteas... | KEEP AS NON CORE | Summary: PINK1 loss increases ROS levels. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:23261939 The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IMP PMID:18560593 PINK1 is necessary for long term survival and mitochondrial ... | KEEP AS NON CORE | Summary: PINK1-deficient neurons show increased ROS. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:18560593 PINK1 deficiency leads to reduced long-term viability in human neurons |
| GO:2001171 positive regulation of ATP biosynthetic process | TAS PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | MARK AS OVER ANNOTATED | Summary: Long-term PINK1 silencing reduced ATP synthesis and autophagic flux. Reason: This reflects an indirect consequence of PINK1 loss (accumulation of dysfunctional mitochondria, oxidative stress) rather than PINK1 directly carrying out or controlling the process. Supporting Evidence: PMID:20871098 Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. |
| GO:2001243 negative regulation of intrinsic apoptotic signaling pathway | IDA PMID:15087508 Hereditary early-onset Parkinson's disease caused by mutatio... | KEEP AS NON CORE | Summary: PINK1 has a protective effect against cellular stress that is abrogated by PD mutations. Reason: PINK1 has well-documented neuroprotective, anti-apoptotic effects (partly through phosphorylation of TRAP1 and other substrates). These are genuine but downstream of, and secondary to, its core role as the damage-sensing kinase that initiates PINK1/Parkin mitophagy. Supporting Evidence: PMID:15087508 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. |
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Download this section (compressed HTML)Q: Which outer-membrane ubiquitinated proteins are the physiologically dominant PINK1 phospho-ubiquitin substrates in neurons in vivo, where basal PINK1-dependent mitophagy appears minor?
Q: How significant are the non-mitophagy PINK1 substrates (TRAP1, Miro, DRP1, complex I subunits) compared with ubiquitin/Parkin in protecting dopaminergic neurons?
Experiment: Quantify pSer65-ubiquitin in sorted dopaminergic neurons of wild-type, PINK1-KO and PINK1 kinase-dead knock-in mice under defined stresses, and correlate with mito-QC mitophagy reporters and neuron survival.
Hypothesis: PINK1-dependent ubiquitin Ser65 phosphorylation in dopaminergic neurons is triggered by physiological stress (e.g. exercise, inflammation, mtDNA stress) and is required for neuronal survival with age.
Type: in vivo phosphoproteomics and mitophagy reporter imaging
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