DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	STK4 (QuickGO)	Interactive visualization of STK4 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 3COM
Synonyms	STK4, KRS2, MST1
Protein Name	STK4
Alternative Name(s)	Serine/threonine-protein kinase 4;2.7.11.1;Mammalian STE20-like protein kinase 1;MST-1;STE20-like kinase MST1;Serine/threonine-protein kinase Krs-2;Serine/threonine-protein kinase 4 37kDa subunit;MST1/N;Serine/threonine-protein kinase 4 18kDa subunit;MST1/C;
Protein Family	Belongs to the protein kinase superfamily STE Ser/Thrprotein kinase family STE20 subfamily
EntrezGene ID	6789 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q13043 (protein sequence)
Enzyme Class	2.7.11.1 (BRENDA )
Molecular Weight	55630 Dalton
Protein Length	487 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000101109 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0201 \| eggNOG - ENOG410XP9G
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Cytoplasm Nucleus Note=The caspase-cleavedform cycles between the nucleus and cytoplasm
Function (UniProt annotation)
Stress-activated, pro-apoptotic kinase which, followingcaspase-cleavage, enters the nucleus and induces chromatincondensation followed by internucleosomal DNA fragmentation Keycomponent of the Hippo signaling pathway which plays a pivotalrole in organ size control and tumor suppression by restrictingproliferation and promoting apoptosis The core of this pathway iscomposed of a kinase cascade wherein STK3/MST2 and STK4/MST1, incomplex with its regulatory protein SAV1, phosphorylates andactivates LATS1/2 in complex with its regulatory protein MOB1,which in turn phosphorylates and inactivates YAP1 oncoprotein andWWTR1/TAZ Phosphorylation of YAP1 by LATS2 inhibits itstranslocation into the nucleus to regulate cellular genesimportant for cell proliferation, cell death, and cell migrationSTK3/MST2 and STK4/MST1 are required to repress proliferation ofmature hepatocytes, to prevent activation of facultative adultliver stem cells (oval cells), and to inhibit tumor formation (Bysimilarity) Phosphorylates 'Ser-14' of histone H2B (H2BS14ph)during apoptosis Phosphorylates FOXO3 upon oxidative stress,which results in its nuclear translocation and cell deathinitiation Phosphorylates MOBKL1A, MOBKL1B and RASSF2Phosphorylates TNNI3 (cardiac Tn-I) and alters its bindingaffinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T)Phosphorylates FOXO1 on 'Ser-212' and regulates its activation andstimulates transcription of PMAIP1 in a FOXO1-dependent mannerPhosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53deacetylation, thereby promoting p53/TP53 dependent transcriptionand apoptosis upon DNA damage Acts as an inhibitor of PKB/AKT1Phosphorylates AR on 'Ser-650' and suppresses its activity byintersecting with PKB/AKT1 signaling and antagonizing formation ofAR-chromatin complexes
Catalytic Activity (UniProt annotation)
ATP + a protein = ADP + a phosphoprotein
Protein Sequence
METVQLRNPPRRQLKKLDEDSLTKQPEEVFDVLEKLGEGSYGSVYKAIHKETGQIVAIKQVPVESDLQEIIKEISIMQQC DSPHVVKYYGSYFKNTDLWIVMEYCGAGSVSDIIRLRNKTLTEDEIATILQSTLKGLEYLHFMRKIHRDIKAGNILLNTE GHAKLADFGVAGQLTDTMAKRNTVIGTPFWMAPEVIQEIGYNCVADIWSLGITAIEMAEGKPPYADIHPMRAIFMIPTNP PPTFRKPELWSDNFTDFVKQCLVKSPEQRATATQLLQHPFVRSAKGVSILRDLINEAMDVKLKRQESQQREVDQDDEENS EEDEMDSGTMVRAVGDEMGTVRVASTMTDGANTMIEHDDTLPSQLGTMVINAEDEEEEGTMKRRDETMQPAKPSFLEYFE QKEKENQINSFGKSVPGPLKNSSDWKIPQDGDYEFLKSWTVEDLQKRLLALDPMMEQEIEEIRQKYQSKRQPILDAIEAK KRRQQNF

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:0000287	F:magnesium ion binding
GO:0000902	P:cell morphogenesis
GO:0001569	P:branching involved in blood vessel morphogenesis
GO:0001841	P:neural tube formation
GO:0001934	P:positive regulation of protein phosphorylation
GO:0003157	P:endocardium development
GO:0004672	F:protein kinase activity
GO:0004674	F:protein serine/threonine kinase activity
GO:0005524	F:ATP binding
GO:0005634	C:nucleus
GO:0005654	C:nucleoplasm
GO:0005737	C:cytoplasm
GO:0005829	C:cytosol
GO:0006468	P:protein phosphorylation
GO:0006915	P:apoptotic process
GO:0007165	P:signal transduction
GO:0007346	P:regulation of mitotic cell cycle
GO:0007417	P:central nervous system development
GO:0008134	F:transcription factor binding
GO:0008285	P:negative regulation of cell proliferation
GO:0016604	C:nuclear body
GO:0018105	P:peptidyl-serine phosphorylation
GO:0023014	P:signal transduction by protein phosphorylation
GO:0030216	P:keratinocyte differentiation
GO:0031098	P:stress-activated protein kinase signaling cascade
GO:0032092	P:positive regulation of protein binding
GO:0032991	C:protein-containing complex
GO:0033138	P:positive regulation of peptidyl-serine phosphorylation
GO:0035329	P:hippo signaling
GO:0035556	P:intracellular signal transduction
GO:0042802	F:identical protein binding
GO:0042803	F:protein homodimerization activity
GO:0043065	P:positive regulation of apoptotic process
GO:0043539	F:protein serine/threonine kinase activator activity
GO:0045600	P:positive regulation of fat cell differentiation
GO:0046621	P:negative regulation of organ growth
GO:0046777	P:protein autophosphorylation
GO:0046983	F:protein dimerization activity
GO:0050821	P:protein stabilization
GO:0060215	P:primitive hemopoiesis
GO:0060706	P:cell differentiation involved in embryonic placenta development
GO:0060800	P:regulation of cell differentiation involved in embryonic placenta development
GO:0090090	P:negative regulation of canonical Wnt signaling pathway
GO:0097284	P:hepatocyte apoptotic process
GO:1902043	P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors
GO:1905461	P:positive regulation of vascular associated smooth muscle 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).
hsa04068	FoxO signaling pathway	The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, methylation and ubiquitylation.
hsa05200	Pathways in cancer
hsa05223	Non-small cell lung cancer	Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.

Pathway ID

Pathway Name

Pathway Description (KEGG)

R-HSA-2028269

Signaling by Hippo.

Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).

There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).

In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.

Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).

In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.

Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010)

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STK4