Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene. [5] [6]
Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene. [5] [6]
Protein kinase activation is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing agents. This protein kinase activation presumably allows cells to resist unfavorable environmental conditions. The yeast 'sterile 20' (Ste20) kinase acts upstream of the mitogen-activated protein kinase (MAPK) cascade that is activated under a variety of stress conditions. MST2 was first identified as a kinase that resembles budding yeast Ste20 (Creasy and Chernoff, 1996) and later as a kinase that is activated by the proapoptotic agents straurosporine and FAS ligand (MIM 134638) (Taylor et al., 1996; Lee et al., 2001).[supplied by OMIM] [6]
Human serine/threonine-protein kinase 3 (STK3, or MST2) is a 56,301 Da [7] monomer with three domains: a SARAH domain, composed of a long α-helix at the C-terminus that when dimerized, forms an antiparallel dimeric coiled-coil, an inhibitory domain, and a catalytic kinase domain at the N-terminus. [8] The SARAH (Salvador/RASSF/Hpo) domain has been found to mediate dimeric interactions between MST2 and RASSF enzymes, a class of tumor suppressors that serve an important role in activating apoptosis, as well as between MST2 and SAV1, a non-catalytic polypeptide responsible for bringing MST2 to an apoptotic pathway. [9] [10] When the MST2 kinase domain is in its active state, a threonine residue residing on an alpha helix at the 180th position (T180) is autophosphorylated. [11]
STK3 is activated through autophosphorylation by dimerizing with itself or heterodimerizing with its homolog, MST1 (STK4). [12] Heterodimerization has been shown to exhibit a roughly six-fold weaker binding affinity than homodimerization with MST2, as well as lower kinase activity compared to both MST2/MST2 and MST1/MST1 homodimers. [10] In addition to activation by straurosporine and FAS ligand, STK3 has been found to be activated through dissociation of GLRX and Thioredoxin (Trx1) from STK3 under oxidative stress. [12] Recent studies have shown that when caspase 3 is activated during apoptosis, MST2 is cleaved, resulting in removal of the regulatory SARAH and inhibitory domains and thus regulation of MST2's kinase activity. Because cleavage by caspase 3 also cleaves off MST2's nuclear export signal, the MST2 kinase fragment can diffuse into the nucleus and phosphorylate Ser14 of histone H2B, promoting apoptosis. [10]
Inactivation of MST2 can be accomplished through inhibition of MST2 homodimerization and autophosphorylation by c-Raf, which binds to the MST2 SARAH domain. [10]
In the mammalian Hippo signaling pathway, MST2, along with its homolog MST1, serves as an upstream kinase whose catalytic activity is responsible for downstream events leading to downregulation of proliferation-associated genes and increased transcription of proapoptotic genes. [12] When MST2 binds to SAV1 through its SARAH domain, MST2 phosphorylates LATS1/LATS2 with the help of SAV1, MOB1A/MOB1B, and Merlin (protein). In turn, LATS1/LATS2 phosphorylates and inhibits YAP1, preventing its movement into the nucleus and activation of transcription of pro-proliferative, anti-apoptotic and migration-associated genes. In the cytoplasm, YAP1 is marked for degradation by the SCF complex. [13] Additionally, MST2 phosphorylates transcription factors in the FOXO (Forkhead box O) family, which diffuse into the nucleus and activate transcription of pro-apoptotic genes. [12]
In many types of cancers, the proto-oncogene c-Raf binds to the SARAH domain of MST2 and prevents RASSF1A-mediated MST2 dimerization and subsequent downstream pro-apoptotic signaling. [14] Research has shown that in cells with loss of PTEN (gene), a tumor suppressor that is frequently mutated in cancers, Akt activity is upregulated, resulting in increased MST2 inactivation and undesirable cell proliferation. [15]
Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.
Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.
Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene. HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors. It belongs to a family of protein kinases known as the DYRK kinases. Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3. HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.
Death-associated protein kinase 1 is an enzyme that in humans is encoded by the DAPK1 gene.
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.
Serine/threonine-protein kinase 4 is an enzyme that in humans is encoded by the STK4 gene.
PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.
Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the RIPK2 gene.
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.
YAP1, also known as YAP or YAP65, is a protein that acts as a transcription coregulator that promotes transcription of genes involved in cellular proliferation and suppressing apoptotic genes. YAP1 is a component in the hippo signaling pathway which regulates organ size, regeneration, and tumorigenesis. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases. YAP1 is a potent oncogene, which is amplified in various human cancers.
Serine-threonine kinase receptor-associated protein is an enzyme that in humans is encoded by the STRAP gene.
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.
Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene. This gene encodes a protein with an important role in the apoptotic pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.
Large tumor suppressor kinase 2 (LATS2) is an enzyme that in humans is encoded by the LATS2 gene.
Serine/threonine protein kinase MST4, also known as mammalian STE20-like protein kinase 4 (MST-4), is a protein that in humans is encoded by the MST4 gene.
Modulator of apoptosis 1 is a protein that in humans is encoded by the MOAP1 gene.
Serine/threonine-protein kinase 24 is an enzyme that in humans is encoded by the STK24 gene located in the chromosome 13, band q32.2. It is also known as Mammalian STE20-like protein kinase 3 (MST-3). The protein is 443 amino acids long and its mass is 49 kDa.
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a "hippopotamus"-like phenotype.