DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	FZR1 (QuickGO)	Interactive visualization of FZR1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 5L9T
Synonyms	FZR1, CDH1, FYR, FZR, KIAA1242
Protein Name	FZR1
Alternative Name(s)	Fizzy-related protein homolog;Fzr;CDC20-like protein 1;Cdh1/Hct1 homolog;hCDH1;
Protein Family	Belongs to the WD repeat CDC20/Fizzy family
EntrezGene ID	51343 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q9UM11 (protein sequence)
Enzyme Class	N/A
Molecular Weight	55179 Dalton
Protein Length	496 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000105325 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0305 \| eggNOG - ENOG410XQ8I
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Motif information from Eukaryotic Linear Motif atlas (ELM)

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Gene Ontology (P: Process; F: Function and C: Component terms)

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KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa04110	Cell cycle	Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated.Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation.
hsa04120	Ubiquitin mediated proteolysis	Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates.
hsa04914	Progesterone-mediated oocyte maturation	Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway [where ERK is an extracellular signal-related protein kinase, MEK is a MAPK/ERK kinase and Mos is a p42(MAPK) activator] and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C.	Cdh1 is degraded by the APC/C during in G1 and G0. This auto-regulation may contribute to reducing the levels of Cdh1 levels during G1 and G0 (Listovsky et al., 2004)
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1.	Emi1 destruction in early mitosis requires the SCF beta-TrCP ubiquitin ligase complex. Binding of beta-TrCP to Emi1 occurs in late prophase and requires phosphorylation at the DSGxxS consensus motif as well as Cdk mediated phosphorylation. A two-step mechanism has been proposed in which the phosphorylation of Emi1 by Cdc2 occurs after the G2-M transition followed soon after by binding of beta-TrCP to the DSGxxS phosphorylation sites. Emi1 is then poly-ubiquitinated and degraded by the 26S proteasome
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1.	From late mitosis through G1 phase APC/C:Cdh1 insures the continued degradation of the mitotic proteins and during mitotic exit and G1 its substrates include Cdc20, Plk1, Aurora A, Cdc6 and Geminin (see Castro et al., 2005). Rape et al. have recently demonstrated that the order in which APC/C targeted proteins are degraded is determined by the processivity of multiubiquitination of these substrates. Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation. In addition, distributive substrates that dissociate from the APC/C with short ubiquitin chains are targeted for deubiquitination (Rape et al., 2006)
R-HSA-176407	Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase.	The activity of the APC/C must be appropriately regulated during the cell cycle to ensure the timely degradation of its substrates. Of particular importance is the conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase. Phosphorylation of both the APC/C complex and Cdh1 regulate this conversion. During mitosis, several APC/C subunits are phosphorylated increasing the activity of APC/C:Cdc20. However, phosphorylation of Cdh1 by mitotic Cyclin:Cdk complexes prevents it from activating the APC/C. Dephosphorylation of Cdh1 in late anaphase by Cdc14a results in the activation of APC/C:Cdh1 (reviewed in Castro et al, 2005)
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase.	The APC/C is activated by either Cdc20 or Cdh1. While both activators associate with the APC/C, they do so at different points in the cell cycle and their binding is regulated differently (see Zachariae and Nasmyth, 1999). Cdc20, whose protein levels increase as cells enter into mitosis and decrease upon mitotic exit, only associates with the APC/C during M phase. Cdh1 associates with the APC/C in G1. This interaction is inhibited at other times by Cdk1 phosphorylation
R-HSA-176417	Phosphorylation of Emi1.	The phosphorylation of Emi1, which is required for its degradation in mitosis, appears to involve both Plk1 and Cdk1
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP).	The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013). Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP. IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008). Please refer to Young and Narita 2009 for a recent review
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6.	As cells enter S phase, HsCdc6p is phosphorylated by CDK promoting its export from the nucleus (see Bell and Dutta 2002)
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry.	Cyclin A:Cdk2 plays a key role in S phase entry by phosphorylation of proteins including Cdh1, Rb, p21 and p27. During G1 phase of the cell cycle, cyclin A is synthesized and associates with Cdk2. After forming in the cytoplasm, the Cyclin A:Cdk2 complexes are translocated to the nucleus (Jackman et al.,2002). Prior to S phase entry, the activity of Cyclin A:Cdk2 complexes is negatively regulated through Tyr 15 phosphorylation of Cdk2 (Gu et al., 1995) and also by the association of the cyclin kinase inhibitors (CKIs), p27 and p21. Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK2 kinase activity (Aprelikova et al., 1995). The entry into S phase is promoted by the removal of inhibitory Tyr 15 phosphates from the Cdk2 subunit of Cyclin A:Cdk2 complex by the Cdc25 phosphatases (Blomberg and Hoffmann, 1999) and by SCF(Skp2)-mediated degradation of p27/p21 (see Ganoth et al., 2001). \r\nWhile Cdk2 is thought to play a primary role in regulating entry into S phase, recent evidence indicates that Cdk1 is equally capable of promoting entry into S phase and the initiation of DNA replication (see Bashir and Pagano, 2005). Thus, Cdk1 complexes may also play a significant role at this point in the cell cycle
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation.	Intracellular foreign or aberrant host proteins are cleaved into peptide fragments of a precise size, such that they can be loaded on to class I MHC molecules and presented externally to cytotoxic T cells. The ubiquitin-26S proteasome system plays a central role in the generation of these class I MHC antigens. Ubiquitination is the mechanism of adding ubiquitin to lysine residues on substrate protein leading to the formation of a polyubiquitinated substrate. This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Polyubiquitination through lysine-48 (K48) generally targets the substrate protein for proteasomal destruction. The protease responsible for the degradation of K48-polyubiquitinated proteins is the 26S proteasome. This proteasome is a two subunit protein complex composed of the 20S (catalytic core) and 19S (regulatory) proteasome complexes. The proteasome eliminates most of the foreign and non-functional proteins from the cell by degrading them into short peptides; only a small fraction of the peptides generated are of the correct length to be presented by the MHC class I system. It has been calculated that between 994 and 3122 protein molecules have to be degraded for the formation of a single, stable MHC class I complex at the cell surface, with an average effciency of 1 in 2000 (Kloetzel et al. 2004, Princiotta et al. 2003)

BioGRID
IntAct
MINT
ALL

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ANAPC2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Reconstituted Complex, electron tomography, ion exchange chromatography, molecular sieving	physical, physical association	12956947, 16287863, 21135578, 25043029, 26083744, 28514442, (Europe PMC)	0.67	BioGRID, IntAct
ANAPC4	Affinity Capture-MS, Affinity Capture-Western, Co-purification, Protein-peptide, pull down	association, physical	12956947, 23078409, 25043029, 25673878, 26083744, 28514442, (Europe PMC)	0.35	BioGRID, IntAct
C7orf25	two hybrid pooling approach	physical association	16169070, (Europe PMC)	0.37	IntAct
CCNB1	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	11562349, 12956947, 14701726, 16921029, 19475398, 20080579, 20383333, 21241890, 21700221, 22014574, 22529100, 23670162, 23708605, 24163370, 25161877, 25241761, 25306923, 25490258, 25825779, 27114510, 27259151, 28514442, (Europe PMC)	0.40	BioGRID, IntAct
CDC14B	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	18662541, (Europe PMC)	0.40	BioGRID, IntAct
CDC16	Affinity Capture-MS, Protein-peptide, anti tag coimmunoprecipitation, tandem affinity purification	association, physical	12956947, 20360068, 26496610, 28514442, (Europe PMC)	0.35	BioGRID, IntAct
CDC23	Affinity Capture-MS, Protein-peptide, anti tag coimmunoprecipitation, tandem affinity purification	association, physical	12956947, 20360068, 26496610, 28514442, (Europe PMC)	0.35	BioGRID, IntAct
CDC26	Affinity Capture-MS, Co-fractionation, Protein-peptide, Reconstituted Complex, tandem affinity purification	association, physical	12956947, 20360068, 25723520, 28514442, (Europe PMC)	0.35	BioGRID, IntAct
CDC27	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical, physical association	11340163, 12097298, 12797865, 12956947, 16479161, 17187060, 17609108, 17942546, 18372912, 18662541, 20395298, 20663873, 21186364, 21241890, 21768287, 21986944, 22014574, 23029392, 23160376, 23670162, 23972993, 24100295, 24811168, 25306918, 26963853, 28514442, 9734353, 9811605, (Europe PMC)	0.84	BioGRID, IntAct
CLSPN	Affinity Capture-Western, Biochemical Activity, anti tag coimmunoprecipitation, pull down	physical, physical association	18662541, 19477924, (Europe PMC)	0.52	BioGRID, IntAct
DNAJA1	two hybrid pooling approach	physical association	16169070, (Europe PMC)	0.37	IntAct
FBXO5	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	11751633, 11988738, 16921029, 23708001, 28514442, (Europe PMC)	0.35	BioGRID, IntAct
MAD2L2	Affinity Capture-Western, Co-fractionation, Reconstituted Complex, anti tag coimmunoprecipitation, pull down	physical, physical association	11459826, 17719540, 24100295, (Europe PMC)	0.52	BioGRID, IntAct
MAK	Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, protein kinase assay	phosphorylation reaction, physical, physical association	21986944, (Europe PMC)	0.60	BioGRID, IntAct
MYC	tandem affinity purification	association	21150319, (Europe PMC)	0.35	IntAct
RAD17	anti bait coimmunoprecipitation	physical association	20424596, (Europe PMC)	0.40	IntAct, MINT
RRM2	Affinity Capture-MS, anti tag coimmunoprecipitation, pull down	association, physical, physical association	22632967, 26186194, 28514442, (Europe PMC)	0.50	BioGRID, IntAct
SIRT2	Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, deacetylase assay	association, direct interaction, physical, physical association	22014574, (Europe PMC)	0.46, 0.54	BioGRID, IntAct
SKP2	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, pull down	physical, physical association	15014502, 19270695, 19686743, 20663873, 21212736, 22770219, 23972993, 28514442, (Europe PMC)	0.40	BioGRID, IntAct
UBE2S	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, pull down	association, physical	19822757, 23708001, 25306918, 25306923, (Europe PMC)	0.35	BioGRID, IntAct
VHL	Affinity Capture-Western, anti bait coimmunoprecipitation, pull down	direct interaction, physical, physical association	20802534, (Europe PMC)	0.40, 0.54	BioGRID, IntAct

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FZR1