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
Controls Rho proteins homeostasis Regulates the GDP/GTPexchange reaction of the Rho proteins by inhibiting thedissociation of GDP from them, and the subsequent binding of GTPto them Retains Rho proteins such as CDC42, RAC1 and RHOA in aninactive cytosolic pool, regulating their stability and protectingthem from degradation Actively involved in the recycling anddistribution of activated Rho GTPases in the cell, mediatesextraction from membranes of both inactive and activated moleculesdue its exceptionally high affinity for prenylated forms Throughthe modulation of Rho proteins, may play a role in cell motilityregulation In glioma cells, inhibits cell migration and invasionby mediating the signals of SEMA5A and PLXNB3 that lead toinactivation of RAC1
Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again.
p75NTR can also form a receptor complex with the Nogo receptor (NgR). Such complexes mediates axonal outgrowth inhibitory signals of MDGIs (myelin-derived growth-inhibitors), such as Nogo66, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP)
The cycling of Rho GTPases is tightly controlled by three classes of protein. These are (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase Activating Proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities.
In their active GTP-bound state, Rho family members have the ability to interact with a large variety of so-called effector proteins. By changing the subcellular localization of effectors, by altering their enzymatic properties, or by directing the formation of specific effector complexes, members of the Rho family mediate their various effects.
This Rho GTPase cycle is diagrammed in the figure below. External or internal cues promote the release of Rho GTPases from the inhibitory complex (1) which allows them to associate with the plasma membrane (2) where they are activated by GEFs (3) and can signal to effector proteins. Then, GAPs inactivate the GTPases by accelerating the intrinsic GTPase activity, leading to the GDP bound form (4). Once again, the GDI molecules stabilize the inactive GDP bound form in the cytoplasm, waiting for further instructions (5). (Figure and text from Tcherkezian and Lamarche Vane, 2007)