DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	TEK (QuickGO)	Interactive visualization of TEK structures (A quick tutorial to explore the interctive visulaization) Representative structure: 5MYA
Synonyms	TEK, TIE2, VMCM, VMCM1
Protein Name	TEK
Alternative Name(s)	Angiopoietin-1 receptor;2.7.10.1;Endothelial tyrosine kinase;Tunica interna endothelial cell kinase;Tyrosine kinase with Ig and EGF homology domains-2;Tyrosine-protein kinase receptor TEK;Tyrosine-protein kinase receptor TIE-2;hTIE2;p140 TEK;CD202b;
Protein Family	Belongs to the protein kinase superfamily Tyr proteinkinase family Tie subfamily
EntrezGene ID	7010 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q02763 (protein sequence)
Enzyme Class	2.7.10.1 (BRENDA )
Molecular Weight	125830 Dalton
Protein Length	1124 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000120156 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0200 \| eggNOG - COG0515
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Cell membrane ; Single-pass type I membrane proteinCell junction Celljunction, focal adhesion Cytoplasm,cytoskeleton Secreted Note=Recruited to cell-cell contacts in quiescent endothelialcells (PubMed:18425120, PubMed:18425119) Colocalizes with theactin cytoskeleton and at actin stress fibers during cellspreading Recruited to the lower surface of migrating cells,especially the rear end of the cell Proteolytic processing givesrise to a soluble extracellular domain that is secreted(PubMed:11806244)
Function (UniProt annotation)
Tyrosine-protein kinase that acts as cell-surfacereceptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis,endothelial cell survival, proliferation, migration, adhesion andcell spreading, reorganization of the actin cytoskeleton, but alsomaintenance of vascular quiescence Has anti-inflammatory effectsby preventing the leakage of proinflammatory plasma proteins andleukocytes from blood vessels Required for normal angiogenesisand heart development during embryogenesis Required for post-natal hematopoiesis After birth, activates or inhibitsangiogenesis, depending on the context Inhibits angiogenesis andpromotes vascular stability in quiescent vessels, whereendothelial cells have tight contacts In quiescent vessels,ANGPT1 oligomers recruit TEK to cell-cell contacts, formingcomplexes with TEK molecules from adjoining cells, and this leadsto preferential activation of phosphatidylinositol 3-kinase andthe AKT1 signaling cascades In migrating endothelial cells thatlack cell-cell adhesions, ANGT1 recruits TEK to contacts with theextracellular matrix, leading to the formation of focal adhesioncomplexes, activation of PTK2/FAK and of the downstream kinasesMAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation ofsprouting angiogenesis ANGPT1 signaling triggers receptordimerization and autophosphorylation at specific tyrosine residuesthat then serve as binding sites for scaffold proteins andeffectors Signaling is modulated by ANGPT2 that has loweraffinity for TEK, can promote TEK autophosphorylation in theabsence of ANGPT1, but inhibits ANGPT1-mediated signaling bycompeting for the same binding site Signaling is also modulatedby formation of heterodimers with TIE1, and by proteolyticprocessing that gives rise to a soluble TEK extracellular domainThe soluble extracellular domain modulates signaling byfunctioning as decoy receptor for angiopoietins TEKphosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Protein Sequence
MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRDFEALMNQHQDPLEVTQDVTR EWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQQASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGS FIHSVPRHEVPDILEVHLPHAQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGEC ICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNEACHPGFYGPDCKLRCSCNNG EMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIEVNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNH TDHFSVAIFTIHRILPPDSGVWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKK LLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTASIGLPPPRGLNLLPKSQTTLN LTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSVLLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPP QPENIKISNITHSSAVISWTILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGS SNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRRMAQAFQNVREEPAVQFNSGT LALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLG HHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQF IHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYC GMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSA EEAA

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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GO:0000165	P:MAPK cascade
GO:0001525	P:angiogenesis
GO:0001666	P:response to hypoxia
GO:0001934	P:positive regulation of protein phosphorylation
GO:0001935	P:endothelial cell proliferation
GO:0001938	P:positive regulation of endothelial cell proliferation
GO:0001958	P:endochondral ossification
GO:0002040	P:sprouting angiogenesis
GO:0004672	F:protein kinase activity
GO:0004713	F:protein tyrosine kinase activity
GO:0004714	F:transmembrane receptor protein tyrosine kinase activity
GO:0005088	F:Ras guanyl-nucleotide exchange factor activity
GO:0005524	F:ATP binding
GO:0005576	C:extracellular region
GO:0005737	C:cytoplasm
GO:0005815	C:microtubule organizing center
GO:0005886	C:plasma membrane
GO:0005887	C:integral component of plasma membrane
GO:0005902	C:microvillus
GO:0005911	C:cell-cell junction
GO:0005925	C:focal adhesion
GO:0007165	P:signal transduction
GO:0007169	P:transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007267	P:cell-cell signaling
GO:0007507	P:heart development
GO:0009925	C:basal plasma membrane
GO:0009986	C:cell surface
GO:0010595	P:positive regulation of endothelial cell migration
GO:0014068	P:positive regulation of phosphatidylinositol 3-kinase signaling
GO:0016323	C:basolateral plasma membrane
GO:0016324	C:apical plasma membrane
GO:0016525	P:negative regulation of angiogenesis
GO:0018108	P:peptidyl-tyrosine phosphorylation
GO:0019838	F:growth factor binding
GO:0032878	P:regulation of establishment or maintenance of cell polarity
GO:0034446	P:substrate adhesion-dependent cell spreading
GO:0038023	F:signaling receptor activity
GO:0043066	P:negative regulation of apoptotic process
GO:0043114	P:regulation of vascular permeability
GO:0043434	P:response to peptide hormone
GO:0043552	P:positive regulation of phosphatidylinositol 3-kinase activity
GO:0043627	P:response to estrogen
GO:0045121	C:membrane raft
GO:0045766	P:positive regulation of angiogenesis
GO:0046777	P:protein autophosphorylation
GO:0048014	P:Tie signaling pathway
GO:0050728	P:negative regulation of inflammatory response
GO:0050900	P:leukocyte migration
GO:0051259	P:protein complex oligomerization
GO:0051591	P:response to cAMP
GO:0051894	P:positive regulation of focal adhesion assembly
GO:0051897	P:positive regulation of protein kinase B signaling
GO:0060216	P:definitive hemopoiesis
GO:0060347	P:heart trabecula formation
GO:0070374	P:positive regulation of ERK1 and ERK2 cascade
GO:0072012	P:glomerulus vasculature development
GO:1902533	P:positive regulation of intracellular signal transduction
GO:2000251	P:positive regulation of actin cytoskeleton reorganization
GO:2000351	P:regulation of endothelial cell apoptotic process
GO:2000352	P:negative regulation of endothelial cell apoptotic process

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa04010	MAPK signaling pathway	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.
hsa04014	Ras signaling pathway	The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
hsa04015	Rap1 signaling pathway	Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
hsa04066	HIF-1 signaling pathway	Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.
hsa04151	PI3K-Akt signaling pathway	The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
hsa05323	Rheumatoid arthritis	Rheumatoid arthritis (RA) is a chronic autoimmune joint disease where persistent inflammation affects bone remodeling leading to progressive bone destruction. In RA, abnormal activation of the immune system elevates pro-inflammatory cytokines and chemokines levels, which can promote synovial angiogenesis and leukocyte infiltration. The synovium forms a hyperplastic pannus with infiltrated macrophage-like and fibroblast-like synoviocytes and invades joints by secreting proteinases and inducing osteoclast differentiation.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-210993	Tie2 Signaling.	The Tie2/Tek receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development and is expressed exclusively on endothelial lineage. Tie2 interacts with a group of ligands belonging to angiopoietin family and undergoes activation.These ligands show opposing actions, angiopoietin 1 and angiopoietin 4 stimulate the Tie2 phosphorylation and angiopoietin 2 inhibits it. Upon tyrosine phosphorylation Tie2 acts as a scaffold for various signaling proteins involved in different signal transduction cascades that can effect survival of endothelium and angiogenic sprout formation
R-HSA-5673001	RAF/MAP kinase cascade.	The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011)

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TEK