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
Cytoplasm Membrane Endosome NucleusNote=Transported into the endosome through interaction withSQSTM1/p62 After phosphorylation by SRC, transported into thenucleus through interaction with KPNB1 Colocalizes with CDK7 inthe cytoplasm and nucleus Transported to vesicular tubularclusters (VTCs) through interaction with RAB2A
Function (UniProt annotation)
Calcium- and diacylglycerol-independent serine/threonine-protein kinase that plays a general protective roleagainst apoptotic stimuli, is involved in NF-kappa-B activation,cell survival, differentiation and polarity, and contributes tothe regulation of microtubule dynamics in the early secretorypathway Is necessary for BCR-ABL oncogene-mediated resistance toapoptotic drug in leukemia cells, protecting leukemia cellsagainst drug-induced apoptosis In cultured neurons, preventsamyloid beta protein-induced apoptosis by interrupting cell deathprocess at a very early step In glioblastoma cells, may functiondownstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 inthe promotion of cell survival by phosphorylating and inhibitingthe pro-apoptotic factor BAD Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 andregulate ECT2 oncogenic activity by phosphorylation, which in turnpromotes transformed growth and invasion In response to nervegrowth factor (NGF), acts downstream of SRC to phosphorylate andactivate IRAK1, allowing the subsequent activation of NF-kappa-Band neuronal cell survival Functions in the organization of theapical domain in epithelial cells by phosphorylating EZR Thisstep is crucial for activation and normal distribution of EZR atthe early stages of intestinal epithelial cell differentiationForms a protein complex with LLGL1 and PARD6B independently ofPARD3 to regulate epithelial cell polarity Plays a role inmicrotubule dynamics in the early secretory pathway throughinteraction with RAB2A and GAPDH and recruitment to vesiculartubular clusters (VTCs) In human coronary artery endothelialcells (HCAEC), is activated by saturated fatty acids and mediateslipid-induced apoptosis
Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
Endocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins entering through clathrin-dependent endocytosis (CDE) have sequences in their cytoplasmic domains that bind to the APs (adaptor-related protein complexes) and enable their rapid removal from the PM. In addition to APs and clathrin, there are numerous accessory proteins including dynamin. Depending on the various proteins that enter the endosome membrane, these cargoes are sorted to distinct destinations. Some cargoes, such as nutrient receptors, are recycled back to the PM. Ubiquitylated membrane proteins, such as activated growth-factor receptors, are sorted into intraluminal vesicles and eventually end up in the lysosome lumen via multivesicular endosomes (MVEs). There are distinct mechanisms of clathrin-independent endocytosis (CIE) depending upon the cargo and the cell type.
Hippo signaling is an evolutionarily conserved signaling pathway that controls organ size from flies to humans. In humans and mice, the pathway consists of the MST1 and MST2 kinases, their cofactor Salvador and LATS1 and LATS2. In response to high cell densities, activated LATS1/2 phosphorylates the transcriptional coactivators YAP and TAZ, promoting its cytoplasmic localization, leading to cell apoptosis and restricting organ size overgrowth. When the Hippo pathway is inactivated at low cell density, YAP/TAZ translocates into the nucleus to bind to the transcription enhancer factor (TEAD/TEF) family of transcriptional factors to promote cell growth and proliferation. YAP/TAZ also interacts with other transcriptional factors or signaling molecules, by which Hippo pathway-mediated processes are interconnected with those of other key signaling cascades, such as those mediated by TGF-beta and Wnt growth factors.
Tight junctions (TJs) are essential for establishing a selectively permeable barrier to diffusion through the paracellular space between neighboring cells. TJs are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. These are proposed to be involved in junction assembly, barrier regulation, cell polarity, gene transcription, and other pathways.
Platelets play a key and beneficial role for primary hemostasis on the disruption of the integrity of vessel wall. Platelet adhesion and activation at sites of vascular wall injury is initiated by adhesion to adhesive macromolecules, such as collagen and von Willebrand factor (vWF), or by soluble platelet agonists, such as ADP, thrombin, and thromboxane A2. Different receptors are stimulated by various agonists, almost converging in increasing intracellular Ca2+ concentration that stimulate platelet shape change and granule secretion and ultimately induce the inside-outsignaling process leading to activation of the ligand-binding function of integrin alpha IIb beta 3. Binding of alpha IIb beta 3 to its ligands, mainly fibrinogen, mediates platelet adhesion and aggregation and triggers outside-insignaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction.
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.
In humans, the NOTCH protein family has four members: NOTCH1, NOTCH2, NOTCH3 and NOTCH4. NOTCH1 protein was identified first, as the product of a chromosome 9 gene translocated in T-cell acute lymphoblastic leukemia that was homologous to Drosophila Notch (Ellisen et al. 1991). At the same time, rat Notch1 was cloned (Weinmaster et al. 1991), followed by cloning of mouse Notch1, named Motch (Del Amo et al. 1992). NOTCH2 protein is the product of a gene on chromosome 1 (Larsson et al. 1994). NOTCH2 expression is differentially regulated during B-cell development (Bertrand et al. 2000). NOTCH2 mutations are a rare cause of Alagille syndrome (McDaniell et al. 2006). NOTCH3 is the product of a gene on chromosome 19. NOTCH3 mutations are the underlying cause of CADASIL, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (Joutel et al. 1996). NOTCH4, the last NOTCH protein discovered, is the product of a gene on chromosome 6 (Li et al. 1998). MicroRNAs play an important negative role in translation and/or stability of NOTCH mRNAs. MicroRNAs miR-34 (miR-34A, miR-34B and mi-R34C), whose transcription is directly induced by the tumor suppressor protein p53 (Chang et al. 2007, Raver-Shapira et al. 2007, He et al. 2007, Corney et al. 2007) bind and negatively regulate translation of NOTCH1 mRNA (Li et al. 2009, Pang et al. 2010, Ji et al. 2009) and NOTCH2 mRNA (Li et al. 2009). NOTCH1 mRNA translation is also negatively regulated by microRNAs miR-200B and miR-200C (Kong et al. 2010), as well as miR-449A, miR-449B and miR-449C (Marcet et al. 2011). Translation of NOTCH3 mRNA is negatively regulated by microRNAs miR-150 (Ghisi et al. 2011) and miR-206 (Song et al. 2009). Translation of NOTCH4 mRNA is negatively regulated by microRNAs miR-181C (Hashimoto et al. 2010) and miR-302A (Costa et al. 2009). Nascent NOTCH peptides are co-translationally targeted to the endoplasmic reticulum for further processing, followed by modification in the Golgi apparatus, before trafficking to the plasma membrane. Endoplasmic reticulum calcium ATPases, positively regulate NOTCH trafficking, possibly by contributing to accurate folding of NOTCH precursors (Periz et al. 1999)
NF-kB activation involves recruitment at the cell membrane of several proteins such as RIP2, MYD88, IRAK1, TRAF6, p62 and atypical PKC by the NGF:p75NTR complex
Tight junctions (TJs) are the most apical component of the epithelial junctional complex forming a belt-like structure at the cellular junction. When visualized by freeze-fracture electron microscopy they appear as a branched network of intramembrane strands that correspond to the sites of direct membrane contacts and that are composed of the integral membrane claudin proteins. The TJs act as a primary barrier to the diffusion of solutes through the paracellular space (barrier function) (Tsukita et al., 2001). They also prevent the intermixing of intramembrane proteins and lipids and thus create a boundary between the apical and the basolateral membrane domains of polarized epithelial cells (fence function) (Tsukita et al., 2001). Interestingly, the fence function seems not to depend on TJ strands (Umeda et al., 2006). Recents evidence indicates that the TJs also participate in signal transduction mechanisms which regulate cell proliferation and morphogenesis (Matter and Balda, 2003; Matter and Balda, 2007). This module describes the major molecular interactions responsible for the formation of TJ strands and for the rectruitment of the PAR-3-PKC-PAR-6 and CRB3-Pals1-PATJ complexes that function in tight junction formation (Ebnet, 2008)
Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, two hybrid, two hybrid array, two hybrid pooling approach, two hybrid prey pooling approach, x-ray crystallography
association, direct interaction, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down, two hybrid, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, FRET, Protein-peptide, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, two hybrid, two hybrid array, two hybrid pooling approach, two hybrid prey pooling approach, x-ray crystallography
association, direct interaction, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down, two hybrid, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, FRET, Protein-peptide, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, two hybrid, two hybrid array, two hybrid pooling approach, two hybrid prey pooling approach, x-ray crystallography
association, direct interaction, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, FRET, Protein-peptide, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, two hybrid, two hybrid array, two hybrid pooling approach, two hybrid prey pooling approach, x-ray crystallography
association, direct interaction, physical, physical association
Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down, two hybrid, two hybrid array, two hybrid prey pooling approach
Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, FRET, Protein-peptide, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, two hybrid array, two hybrid prey pooling approach
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