InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: STK4

Summary

InnateDB Protein

IDBP-77186.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

STK4

Protein Name

serine/threonine kinase 4

Synonyms

KRS2; MST1; TIIAC; YSK3;

Species

Homo sapiens

Ensembl Protein

ENSP00000361892

InnateDB Gene

IDBG-77184 (STK4)

Protein Structure

UniProt Annotation

Function

Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes. {ECO:0000250, ECO:0000269PubMed:11278283, ECO:0000269PubMed:11517310, ECO:0000269PubMed:12757711, ECO:0000269PubMed:15109305, ECO:0000269PubMed:16510573, ECO:0000269PubMed:16751106, ECO:0000269PubMed:16930133, ECO:0000269PubMed:17932490, ECO:0000269PubMed:18328708, ECO:0000269PubMed:18986304, ECO:0000269PubMed:19525978, ECO:0000269PubMed:21212262, ECO:0000269PubMed:21245099, ECO:0000269PubMed:21512132, ECO:0000269PubMed:8702870, ECO:0000269PubMed:8816758}.

Subcellular Localization

Cytoplasm. Nucleus. Note=The caspase-cleaved form cycles between the nucleus and cytoplasm.

Disease Associations

T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations (TIIAC) [MIM:614868]: A primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T-cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect. {ECO:0000269PubMed:22294732}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Ubiquitously expressed. {ECO:0000269PubMed:17932490}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 106 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Experimentally validated
Total	106 [view]
Protein-Protein	105 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000287	magnesium ion binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008134	transcription factor binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042802	identical protein binding
GO:0042803	protein homodimerization activity
GO:0043539	protein serine/threonine kinase activator activity
GO:0046983	protein dimerization activity

Biological Process

GO:0000902	cell morphogenesis
GO:0001569	patterning of blood vessels
GO:0001841	neural tube formation
GO:0003157	endocardium development
GO:0006468	protein phosphorylation
GO:0006915	apoptotic process
GO:0007165	signal transduction
GO:0007417	central nervous system development
GO:0008285	negative regulation of cell proliferation
GO:0018105	peptidyl-serine phosphorylation
GO:0023014	signal transduction by phosphorylation
GO:0030216	keratinocyte differentiation
GO:0035329	hippo signaling
GO:0035556	intracellular signal transduction
GO:0043065	positive regulation of apoptotic process
GO:0046621	negative regulation of organ growth
GO:0046777	protein autophosphorylation
GO:0060215	primitive hemopoiesis
GO:0060706	cell differentiation involved in embryonic placenta development
GO:0071902	positive regulation of protein serine/threonine kinase activity
GO:0090090	negative regulation of canonical Wnt signaling pathway
GO:0097284	hepatocyte apoptotic process
GO:1902043	positive regulation of extrinsic apoptotic signaling pathway via death domain receptors

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR011524 SARAH domain
IPR020635 Tyrosine-protein kinase, catalytic domain
IPR024205 Mst1 SARAH domain

PFAM

PF00069
PF07714
PF11629

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt