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
Inactivates MAP kinases Has a specificity for the ERKfamily (PubMed:9858808) Plays an important role in alleviatingchronic postoperative pain Necessary for the normaldephosphorylation of the long-lasting phosphorylated forms ofspinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery,which drives the resolution of acute postoperative allodynia (Bysimilarity) Also important for dephosphorylation of MAPK1/3 inlocal wound tissue, which further contributes to resolution ofacute pain (By similarity)
The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
In tumor cells, genes encoding transcription factors (TFs) are often amplified, deleted, rearranged via chromosomal translocation and inversion, or subjected to point mutations that result in a gain- or loss-of- function. In hematopoietic cancers and solid tumors, the translocations and inversions increase or deregulate transcription of the oncogene. Recurrent chromosome translocations generate novel fusion oncoproteins, which are common in myeloid cancers and soft-tissue sarcomas. The fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors alter expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process.
Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
Depending upon the stimulus and cell type mitogen-activated protein kinases (MAPK) signaling pathway can transmit signals to regulate many different biological processes by virtue of their ability to target multiple effector proteins (Kyriakis JM & Avruch J 2012; Yoon and Seger 2006; Shaul YD & Seger R 2007; Arthur JS & Ley SC 2013). In particular, the extracellular signal-regulated kinases MAPK3(ERK1) and MAPK1 (ERK2) are involved in diverse cellular processes such as proliferation, differentiation, regulation of inflammatory responses, cytoskeletal remodeling, cell motility and invasion through the increase of matrix metalloproteinase production (Viala E & Pouyssegur J 2004; Hsu MC et al. 2006; Dawson CW et al.2008; Kuriakose T et al. 2014).The canonical RAF:MAP2K:MAPK1/3 cascade is stimulated by various extracellular stimuli including hormones, cytokines, growth factors, heat shock and UV irradiation triggering the GEF-mediated activation of RAS at the plasma membrane and leading to the activation of the RAF MAP3 kinases. However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS (Dawson CW et al. 2008; Wang J et al. 2009; Kuriakose T et al. 2014). For example, AMP-activated protein kinase (AMPK), but not RAF1, was reported to regulate MAP2K1/2 and MAPK1/3 (MEK and ERK) activation in rat hepatoma H4IIE and human erythroleukemia K562 cells in response to autophagy stimuli (Wang J et al. 2009). Tumor progression locus 2 (TPL2, also known as MAP3K8 and COT) is another MAP3 kinase which promotes MAPK1/3 (ERK)-regulated immune responses downstream of toll-like receptors (TLR), TNF receptor and IL1beta signaling pathways (Gantke T et al. 2011).
In response to stimuli the cell surface receptors transmit signals inducing MAP3 kinases, e.g., TPL2, MEKK1, which in turn phosphorylate MAP2Ks (MEK1/2). MAP2K then phosphorylate and activate the MAPK1/3 (ERK1 and ERK2 MAPKs). Activated MAPK1/3 phosphorylate and regulate the activities of an ever growing pool of substrates that are estimated to comprise over 160 proteins (Yoon and Seger 2006). The majority of ERK substrates are nuclear proteins, but others are found in the cytoplasm and other organelles. Activated MAPK1/3 can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, such as Ets family transcription factors (e.g., ELK1), ultimately leading to changes in gene expression (Zuber J et al. 2000)
MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK
The duration and extent of activated MAPK signaling is regulated at many levels through mechanisms that include phosphorylation and dephosphorylation, changes to protein interacting partners and subcellular localization (reviewed in Matallanas et al, 2011). Activated RAF proteins are subject to MAPK-dependent phosphorylation that promotes the subsequent dephosphorylation of the activation loop and NtA region, terminating RAF kinase activity. This dephosphorylation, catalyzed by PP2A and PP5, primes the RAF proteins for PKA or AKT-mediated phosphorylation of residues S259 and S621, restoring the 14-3-3 binding sites and returning the RAF proteins to the inactive state (von Kriegsheim et al, 2006; Dougherty et al, 2005; reviewed in Matallanas et al, 2011). The phosphorylated RAF1 NtA is also subject to additional regulation through binding to the PEBP1 protein, which promotes its dissociation from MAP2K substrates (Shin et al, 2009). Activated MAPK proteins also phosphorylate T292 of MAP2K1; this phosphorylation limits the activity of MAP2K1, and indirectly affects MAP2K2 activity through by modulating the activity of the MAP2K heterodimer (Catalanotti et al, 2009; reviewed in Matallanas et al, 2011).Dephosphorylation of MAPKs by the dual specificity MAPK phosphatases (DUSPs) plays a key role in limiting the extent of pathway activation (Owens et al, 2007; reviewed in Roskoski, 2012b). Class I DUSPs are localized in the nucleus and are induced by activation of the MAPK pathway, establishing a negative feedback loop, while class II DUSPs dephosphorylate cytoplasmic MAPKs (reviewed in Rososki, 2012b).MAPK signaling is also regulated by the RAS GAP-mediated stimulation of intrinsic RAS GTPase activity which returns RAS to the inactive, GDP bound state (reviewed in King et al, 2013)
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