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
Transcription factor involved in osteoblasticdifferentiation and skeletal morphogenesis (PubMed:28505335,PubMed:28738062, PubMed:28703881) Essential for the maturation ofosteoblasts and both intramembranous and endochondralossification CBF binds to the core site, 5'-PYGPYGGT-3', of anumber of enhancers and promoters, including murine leukemiavirus, polyomavirus enhancer, T-cell receptor enhancers,osteocalcin, osteopontin, bone sialoprotein, alpha 1(I) collagen,LCK, IL-3 and GM-CSF promoters In osteoblasts, supportstranscription activation: synergizes with SPEN/MINT to enhanceFGFR2-mediated activation of the osteocalcin FGF-responsiveelement (OCFRE) (By similarity) Inhibits KAT6B-dependenttranscriptional activation
Parathyroid hormone (PTH) is a key regulator of calcium and phosphorus homeostasis. The principal regulators of PTH secretion are extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). Under conditions of dietary Ca restriction, a decrement in serum Ca concentration induces release of PTH from the parathyroid gland. PTH acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25(OH)2D3 and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. This hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R). PTH1R primarily activates two sub-types of heterotrimeric Gproteins: Gs and Gq , which in turn regulate the activity of adenylyl cyclases and phospholipase C (PLC) that control the flow of cAMP/PKA and IP/PKC signaling cascades, respectively.
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.
YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010)
RUNX2 (CBFA1 or AML3) transcription factor, similar to other RUNX family members, RUNX1 and RUNX3, can function in complex with CBFB (CBF-beta) (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002). RUNX2 mainly regulates transcription of genes involved in skeletal development (reviewed in Karsenty 2008). RUNX2 is involved in development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. RUNX2 stimulates transcription of the BGLAP gene (Ducy and Karsenty 1995, Ducy et al. 1997), which encodes Osteocalcin, a bone-derived hormone which is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). RUNX2 directly controls the expression of most genes associated with osteoblast differentiation and function (Sato et al. 1998, Ducy et al. 1999, Roce et al. 2005). RUNX2-mediated transcriptional regulation of several genes involved in GPCR (G protein coupled receptor) signaling is implicated in the control of growth of osteoblast progenitors (Teplyuk et al. 2009). RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004). Germline loss-of-function mutations of the RUNX2 gene are associated with cleidocranial dysplasia syndrome (CCD), an autosomal skeletal disorder (reviewed in Jaruga et al. 2016). The function of RUNX2 is frequently disrupted in osteosarcoma (reviewed in Mortus et al. 2014). Vitamin D3 is implicated in regulation of transcriptional activity of the RUNX2:CBFB complex (Underwood et al. 2012).
RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).
RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).
RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).
For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015
The RUNX1:CBFB complex regulates expression of genes involved in differentiation of myeloid progenitors which can commit to hematopoietic lineages that lead to generation of platelets, erythrocytes, leukocytes or monocytes.The RUNX1:CBFB complex recruits histone acetyltransferase CREBBP (CBP) to the promoter of the CSF2 gene, encoding Granulocyte-macrophage colony stimulating factor (GM-CSF), thus inducing GM-CSF expression (Oakford et al. 2010). GM-CSF induces growth, differentiation and survival of macrophages, granulocytes, erythrocytes and megakaryocytes from myeloid progenitors (Barreda et al. 2004).The RUNX1:CBFB complex directly stimulates transcription of the LGALS3 gene, encoding galectin-3 (Zhang et al. 2009). Galectin-3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).The PRKCB gene, encoding protein kinase C-beta, which regulates apoptosis of myeloid cells, is directly transactivated by the RUNX1:CBFB complex (Hu et al. 2004)
Several transcription factors have been implicated in regulation of the RUNX2 gene transcription. Similar to the RUNX1 gene, the RUNX2 gene expression can be regulated from the proximal P2 promoter or the distal P1 promoter (reviewed in Li and Xiao 2007).Activated estrogen receptor alpha (ESR1) binds estrogen response elements (EREs) in the P2 promoter and stimulates RUNX2 transcription (Kammerer et al. 2013). Estrogen-related receptor alpha (ERRA) binds EREs or estrogen-related response elements (ERREs) in the P2 promoter of RUNX2. When ERRA is bound to its co-factor PPARG1CA (PGC1A), it stimulates RUNX2 transcription. When bound to its co-factor PPARG1CB (PGC1B), ERRA represses RUNX2 transcription (Kammerer et al. 2013).TWIST1, a basic helix-loop-helix (bHLH) transcription factor, stimulates RUNX2 transcription by binding to the E1-box in the P2 promoter (Yang, Yang et al. 2011). TWIST proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004). Schnurri-3 (SHN3) is another protein that interacts with RUNX2 to decrease its availability in the nucleus and therefore its activity (Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006). Formation of the heterodimer with CBFB (CBF-beta) also enhances the transcriptional activity of RUNX2 (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002).Transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012).NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene and inhibits its transcription (Lengner et al. 2005). RUNX2-P1 transcription is also autoinhibited by RUNX2-P1, which binds to RUNX2 response elements in the P1 promoter of RUNX2 (Drissi et al. 2000). In contrast, binding of RUNX2-P2 to the proximal P2 promoter autoactivates transcription of RUNX2-P2 (Ducy et al. 1999). Binding of a homeodomain transcription factor DLX5, and possibly DLX6, to the RUNX2 P1 promoter stimulates RUNX2 transcription (Robledo et al. 2002, Lee et al. 2005). The homeobox transcription factor MSX2 can bind to DLX5 sites in the promoter of RUNX2 and inhibit transcription of RUNX2-P1 (Lee et al. 2005).Translocation of RUNX2 protein to the nucleus is inhibited by binding to non-activated STAT1 (Kim et al. 2003).Several E3 ubiquitin ligases were shown to polyubiquitinate RUNX2, targeting it for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016)
The complex of RUNX2 and CBFB regulates transcription of genes involved in differentiation of osteoblasts.RUNX2 stimulates transcription of the BGLAP gene, encoding osteocalcin (Ducy and Karsenty 1995, Ducy et al. 1997). Binding of the RUNX2:CBFB complex to the BGLAP gene promoter is increased when RUNX2 is phosphorylated on serine residue S451 (Wee et al. 2002). Osteocalcin, a bone-derived hormone, is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). Association of the activated androgen receptor (AR) with RUNX2 prevents binding of RUNX2 to the BGLAP promoter (Baniwal et al. 2009). When YAP1, tyrosine phosphorylated by SRC and/or YES1, binds to RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited (Zaidi et al. 2004). Signaling by SRC is known to inhibit osteoblast differentiation (Marzia et al. 2000).Simultaneous binding of RUNX2 and SP7 (Osterix, also known as OSX) to adjacent RUNX2 and SP7 binding sites, respectively, in the UCMA promoter, synergistically activates UCMA transcription. UCMA stimulates osteoblast differentiation and formation of mineralized nodules (Lee et al. 2015).The SCF(SKP2) E3 ubiquitin ligase complex inhibits differentiation of osteoblasts by polyubiquitinating RUNX2 and targeting it for proteasome-mediated degradation (Thacker et al. 2016). This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015)
In addition to regulating osteoblast differentiation, RUNX2 regulates skeletal development by regulating maturation of chondrocytes (Takeda et al. 2001). Chondrocyte maturation happens during the process of endochondral ossification. Expression of the parathyroid hormone receptor (PTHR1) and Indian hedgehog (IHH) are hallmarks of chondrocyte maturation. Mice that are double knockouts for Runx2 and Runx3 show a complete absence of chondrocyte maturation and, hence, aberrant limb growth. Based on mouse studies, RUNX2 directly regulates transcription of the IHH gene. RUNX2 binding sites in the IHH gene promoter are conserved in humans (Yoshida et al. 2004). Also based on mouse studies, RUNX2 positively regulates transcription of NELL1 (neural EGFL-like 1), a key functional mediator of chondrogenesis, but direct binding of RUNX2 to the NELL1 gene locus has not been demonstrated (Li et al. 2017). Runx2 binding sites exist in the enhancer of the mouse Col10a1 gene, encoding type X collagen, a marker of hypertrophic chondrocytes, which is critical for endochondral bone formation. While Runx2 binding is required, it is not sufficient to trigger Col10a1 transcription (Gu et al. 2014)
RUNX2 is required for the development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. In its absence, intramembraneous ossification is blocked while endochondral ossification is arrested at the cartilaginous stage (Otto et al. 1997, Komori et al. 1997). In mice and humans, RUNX2 haploinsufficiency causes Cleidocranial dysplasia, a generalized bone disorder (Otto et al. 1997, Lee et al. 1997).RUNX2 stimulates transcription of most of the genes constituting the bone extracellular matrix and of BGLAP gene, which encodes Osteocalcin, a bone-derived hormone controlling glucose metabolism, male fertility and cognition (Ducy et al. 1997).RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004).In response to BMP2 signaling, RUNX2 forms a complex with SMAD1:SMAD4 heterotrimer in the nucleus and stimulates transcription of SMAD6 (Wang et al. 2007).RBM14, a negative regulator of RUNX2 transcriptional activity, is frequently overexpressed in osteosarcoma (Li et al. 2009)
RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells.RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5. Integrin alpha-5 promotes adhesion of breast cancer cells to the bone, thus facilitating formation of bone metastases (Li et al. 2016). ITGA5 is implicated in migration of human dental pulp stem cells (Xu et al. 2015). In zebrafish, Integrin alpha-5 coordinates cell migration during development of sensory organs (Bhat et al. 2011). During mouse retinal angiogenesis, Integrin alpha-5 regulates migration of endothelial cells (Stenzel et al. 2011).The ITGBL1 gene encodes Integrin beta like protein 1, which is implicated in regulation of TGF-beta signaling and RUNX2-induced bone metastasis of breast cancer (Li et al. 2015).RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 and is implicated in invasiveness of breast cancer cells (Pande et al. 2013). MMP13 is involved in migration of innate immune system cells in response to injury (Zhang et al. 2008) and in remodelling of skeletal tissues (Ortega et al. 2003)
Both RUNX2 and RUNX1 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000). Galectin 3 is highly expressed in pituitary tumors and glioma (Vladimirova et al. 2008, Zhang et al. 2009)
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