241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
299 KEGG pathways;
876 Reactome pathways;
last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Cell membrane ; Single-pass type I membrane protein
Function (UniProt annotation)
Cell-surface glycoprotein having a role inimmunoadhesion Mediates in the adhesion of blood neutrophils incytokine-activated endothelium through interaction withSELPLG/PSGL1 May have a role in capillary morphogenesis
Cell adhesion molecules are (glyco)proteins expressed on the cell surface and play a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation, embryogenesis, and development of neuronal tissue. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. Membrane proteins that mediate immune cell–cell interactions fall into different categories, namely those involved in antigen recognition, costimulation and cellular adhesion. Furthermore cell-cell adhesions are important for brain morphology and highly coordinated brain functions such as memory and learning. During early development of the nervous system, neurons elongate their axons towards their targets and establish and maintain synapses through formation of cell-cell adhesions. Cell-cell adhesions also underpin axon-axon contacts and link neurons with supporting schwann cells and oligodendrocytes.
Tumor necrosis factor (TNF), as a critical cytokine, can induce a wide range of intracellular signal pathways including apoptosis and cell survival as well as inflammation and immunity. Activated TNF is assembled to a homotrimer and binds to its receptors (TNFR1, TNFR2) resulting in the trimerization of TNFR1 or TNFR2. TNFR1 is expressed by nearly all cells and is the major receptor for TNF (also called TNF-alpha). In contrast, TNFR2 is expressed in limited cells such as CD4 and CD8 T lymphocytes, endothelial cells, microglia, oligodendrocytes, neuron subtypes, cardiac myocytes, thymocytes and human mesenchymal stem cells. It is the receptor for both TNF and LTA (also called TNF-beta). Upon binding of the ligand, TNFR mediates the association of some adaptor proteins such as TRADD or TRAF2, which in turn initiate recruitment of signal transducers. TNFR1 signaling induces activation of many genes, primarily controlled by two distinct pathways, NF-kappa B pathway and the MAPK cascade, or apoptosis and necroptosis. TNFR2 signaling activates NF-kappa B pathway including PI3K-dependent NF-kappa B pathway and JNK pathway leading to survival.
Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications.
Trypanosoma brucei, the parasite responsible for African trypanosomiasis (sleeping sickness), are spread by the tsetse fly in sub-Saharan Africa. The parasites are able to pass through the blood-brain barrier and cause neurological damage by inducing cytokines like TNF alpha, IFN gamma, and IL1. These cytokines and other metabolites such as nitric oxide and somnogenic prostaglandin D2 disturb circadian rhythms in patients with African trypanosomiasis.
Plasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop into the merozoite form.Sporozoite invasion of hepatocytes is mediated by parasite surface protein like CSP. Subsequent infection into red blood cells (RBCs) by merozoites causes malaria disease via aberrant cytokine production and sequestration of parasite-infected red blood cells (pRBCs) to host endothelium. Microvasculature sequestration in the brain brings about cerebral malaria that can results in death or persisting neurological impairment. PfEMP1 has been suggested as the key adhesive molecule of pRBCs.
Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).
Leukocyte extravasation is a rigorously controlled process that guides white cell movement from the vascular lumen to sites of tissue inflammation. The powerful adhesive interactions that are required for leukocytes to withstand local flow at the vessel wall is a multistep process mediated by different adhesion molecules. Platelets adhered to injured vessel walls form strong adhesive substrates for leukocytes. For instance, the initial tethering and rolling of leukocytes over the site of injury are mediated by reversible binding of selectins to their cognate cell-surface glycoconjugates.
\r\n\r\nEndothelial cells are tightly connected through various proteins, which regulate the organization of the junctional complex and bind to cytoskeletal proteins or cytoplasmic interaction partners that allow the transfer of intracellular signals. An important role for these junctional proteins in governing the transendothelial migration of leukocytes under normal or inflammatory conditions has been established.
\r\n\r\nThis pathway describes some of the key interactions that assist in the process of platelet and leukocyte interaction with the endothelium, in response to injury