241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Involved in the activation cascade of caspasesresponsible for apoptosis execution Might function by eitheractivating some proteins required for cell death or inactivatingproteins necessary for cell survival
Catalytic Activity (UniProt annotation)
Strict requirement for an Asp residue at P1,with 316-asp being essential for proteolytic activity and has apreferred cleavage sequence of Val-Asp-Val-Ala-Asp-|-
Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators
NADE protein (p75NTR-associated cell death executor) may induce cell death upon NGF binding, but not BDNF, NT3, or NT4/5 binding, to p75NTR. The NADE-dependent apoptosis is modulated by the 14-3-3-epsilon protein (Kimura MT et al, 2001)
TP53 (p53) transcriptionally regulates cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10. These caspases and their activators are involved either in the intrinsic apoptosis pathway or in the extrinsic apoptosis pathway triggerred by death receptors or the inflammation-related cell death pyroptosis (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007)
Biochemical Activity, Two-hybrid, anti tag coimmunoprecipitation, bimolecular fluorescence complementation, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
Affinity Capture-Western, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, coimmunoprecipitation, molecular sieving, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
association, genetic, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, fluorescence microscopy
Affinity Capture-Western, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, coimmunoprecipitation, molecular sieving, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
association, genetic, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, fluorescence microscopy
Affinity Capture-Western, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, coimmunoprecipitation, molecular sieving, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
association, genetic, physical, physical association
Biochemical Activity, Two-hybrid, anti tag coimmunoprecipitation, bimolecular fluorescence complementation, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
Affinity Capture-Western, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, coimmunoprecipitation, molecular sieving, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid
association, genetic, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, affinity chromatography technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, fluorescence microscopy
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