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
Cell membrane Cell projection, axon Cell projection, dendrite Celljunction, synapse, postsynaptic cell membrane, postsynapticdensity Early endosome Note=Clustered upon activation and targeted to early endosome
Function (UniProt annotation)
Receptor tyrosine kinase which binds membrane-boundephrin family ligands residing on adjacent cells, leading tocontact-dependent bidirectional signaling into neighboring cellsThe signaling pathway downstream of the receptor is referred to asforward signaling while the signaling pathway downstream of theephrin ligand is referred to as reverse signaling Highlypromiscuous, it has the unique property among Eph receptors tobind and to be physiologically activated by both GPI-anchoredephrin-A and transmembrane ephrin-B ligands including EFNA1 andEFNB3 Upon activation by ephrin ligands, modulates cellmorphology and integrin-dependent cell adhesion through regulationof the Rac, Rap and Rho GTPases activity Plays an important rolein the development of the nervous system controlling differentsteps of axonal guidance including the establishment of thecorticospinal projections May also control the segregation ofmotor and sensory axons during neuromuscular circuit developmentIn addition to its role in axonal guidance plays a role insynaptic plasticity Activated by EFNA1 phosphorylates CDK5 at'Tyr-15' which in turn phosphorylates NGEF regulating RHOA anddendritic spine morphogenesis In the nervous system, plays also arole in repair after injury preventing axonal regeneration and inangiogenesis playing a role in central nervous system vascularformation Additionally, its promiscuity makes it available toparticipate in a variety of cell-cell signaling regulating forinstance the development of the thymic epithelium
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn.
During the development process cell migration and adhesion are the main forces involved in morphing the cells into critical anatomical structures. The ability of a cell to migrate to its correct destination depends heavily on signaling at the cell membrane. Erythropoietin producing hepatocellular carcinoma (EPH) receptors and their ligands, the ephrins (EPH receptors interacting proteins, EFNs), orchestrates the precise control necessary to guide a cell to its destination. They are expressed in all tissues of a developing embryo and are involved in multiple developmental processes such as axon guidance, cardiovascular and skeletal development and tissue patterning. In addition, EPH receptors and EFNs are expressed in developing and mature synapses in the nervous system, where they may have a role in regulating synaptic plasticity and long-term potentiation. Activation of EPHB receptors in neurons induces the rapid formation and enlargement of dendritic spines, as well as rapid synapse maturation (Dalva et al. 2007). On the other hand, EPHA4 activation leads to dendritic spine elimination (Murai et al. 2003, Fu et al. 2007).EPH receptors are the largest known family of receptor tyrosine kinases (RTKs), with fourteen total receptors divided into either A- or B-subclasses: EPHA (1-8 and 10) and EPHB (1-4 and 6). EPH receptors can have overlapping functions, and loss of one receptor can be partially compensated for by another EPH receptor that has similar expression pattern and ligand-binding specificities. EPH receptors have an N-terminal extracellular domain through which they bind to ephrin ligands, a short transmembrane domain, and an intracellular cytoplasmic signaling structure containing a canonical tyrosine kinase catalytic domain as well as other protein interaction sites. Ephrins are also sub-divided into an A-subclass (A1-A5), which are tethered to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor, and a B-subclass (B1-B3), members of which have a transmembrane domain and a short, highly conserved cytoplasmic tail lacking endogenous catalytic activity. The interaction between EPH receptors and its ligands requires cell-cell interaction since both molecules are membrane-bound. Close contact between EPH receptors and EFNs is required for signaling to occur. EPH/EFN-initiated signaling occurs bi-directionally into either EPH- or EFN-expressing cells or axons. Signaling into the EPH receptor-expressing cell is referred as the forward signal and signaling into the EFN-expressing cell, the reverse signal. (Dalva et al. 2000, Grunwald et al. 2004, Davy & Robbins 2000, Cowan et al
EPH/Ephrin signaling is coupled to Rho family GTPases such as Rac, Rho and Cdc42 that connect bidirectional receptor-ligand interactions to changes in the actin cytoskeleton (Noren & Pasquale 2004, Groeger & Nobes 2007). RHOA regulates actin dynamics and is involved in EPHA-induced growth cone collapse. This is mediated by ephexins. Ephexin, a guanine nucleotide exchange factor for Rho GTPases, interacts with the EPHA kinase domain and its subsequent activation differentially affects Rho GTPases, such that RHOA is activated, whereas Cdc42 and Rac1 are inhibited. Activation of RHOA, and inhibition of Cdc42 and Rac, shifts actin cytoskeleton to increased contraction and reduced expansion leading to growth-cone collapse (Shamah et al. 2001, Sahin et al. 2005). The activation of EPH receptors in growing neurons typically, but not always, leads to a growth cone collapse response and retraction from an ephrin-expressing substrate (Poliakov et al. 2004, Pasquale 2005). EPHA-mediated repulsive responses prevent axons from growing into regions of excessive ephrin-A concentration, such as the posterior end of the superior colliculus (Pasquale 2005)
Despite high-affinity multimeric interaction between EPHs and ephrins (EFNs), the cellular response to EPH-EFN engagement is usually repulsion between the two cells and signal termination. These repulsive responses induce an EPH receptor-expressing cell to retract from an ephrin-expressing cell after establishing initial contact. The repulsive responses mediated by EPH receptors in the growth cone at the leading edge of extending axons and in axonal collateral branches contribute to the formation of selective neuronal connections. It is unclear how high affinity trans-cellular interactions between EPHs and ephrins are broken to convert adhesion into repulsion. Two possible mechanisms have been proposed for the repulsion of EPH-EFN bearing cells: the first one involves regulated cleavage of ephrin ligands or EPH receptors by transmembrane proteases following cell-cell contact, while the second one is rapid endocytosis of whole EPH:EFN complexes during the retraction of the interacting cells or neuronal growth cones (Egea & Klein 2007, Janes et al. 2005). RAC also plays an essential role during growth cone collapse by promoting actin polymerization that drives membrane internalization by endocytosis (Marston et al. 2003)
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