C-Jun N-terminal kinases
Encyclopedia
c-Jun N-terminal kinases (JNKs), were originally identified as kinase
s that bind and phosphorylate
c-Jun
on Ser
-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase
family, and are responsive to stress stimuli, such as cytokines, ultraviolet
irradiation, heat shock, and osmotic shock. They also play a role in T cell
differentiation and the cellular apoptosis
pathway. Activation occurs through a dual phosphorylation of threonine
(Thr) and tyrosine
(Tyr) residues within a Thr-Pro
-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinases, MKK4 and MKK7 and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases
. It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.
derived from three genes: JNK1
(four isoforms), JNK2
(four isoforms) and JNK3
(two isoforms). Each gene is expressed as either 46 kDa or 55 kDa protein kinases, depending upon how the 3' coding region of the corresponding mRNA is processed. There have been no functional differences documented between the 46 kDa and the 55 kDa isoform, however, a second form of alternative splicing occurs within transcripts of JNK1 and JNK2, yielding JNK1-α, JNK2-α and JNK1-β and JNK2-β. Differences in interactions with protein substrates arise because of the mutually exclusive utilization of two exon
s within the kinase domain.
c-Jun N-terminal kinase isoforms have the following tissue distribution:
JNKs can associate with scaffold protein
s JNK interacting proteins as well as their upstream kinases JNKK1
and JNKK2
following their activation.
JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Downstream molecules that are activated by JNK include c-Jun
, ATF2
, ELK1
, SMAD4
, p53
and HSF1
. The downstream molecules that are inhibited by JNK activation include NFAT4
, NFATC1
and STAT3
. By activating and inhibiting other small molecules in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis.
JNK1 is involved in apoptosis
, neurodegeneration
, cell differentiation and proliferation, inflammatory conditions and cytokine
production mediated by AP-1 (activation protein 1) such as RANTES
, IL-8
and GM-CSF.
Recently, JNK1 has been found to regulate Jun
protein turnover
by phosphorylation
and activation of the ubiquitin ligase
Itch
.
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s that bind and phosphorylate
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
c-Jun
C-jun
c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...
on Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
family, and are responsive to stress stimuli, such as cytokines, ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
irradiation, heat shock, and osmotic shock. They also play a role in T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
differentiation and the cellular apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
pathway. Activation occurs through a dual phosphorylation of threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
(Thr) and tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
(Tyr) residues within a Thr-Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-Tyr motif located in kinase subdomain VIII. Activation is carried out by two MAP kinases, MKK4 and MKK7 and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
. It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects.
Isoforms
The c-Jun N-terminal kinases consist of ten isoformsProtein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
derived from three genes: JNK1
MAPK8
Mitogen-activated protein kinase 8 is an enzyme that in humans is encoded by the MAPK8 gene.-Interactions:MAPK8 has been shown to interact with SPIB, DUSP1, Activating transcription factor 2, SH3BP5, GSTP1, MAPK8IP1, MAP2K7, CRK, MAP2K4, DUSP22, Myc, MAP3K2, DUSP10, REL, MAPK8IP3, IRS1, MAP3K1 and...
(four isoforms), JNK2
Mitogen-activated protein kinase 9
Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.-Interactions:Mitogen-activated protein kinase 9 has been shown to interact with TOB1, Grb2, MAPK8IP2, P53, MAPK8IP3 and MAPK8IP1.-Further reading:...
(four isoforms) and JNK3
MAPK10
Mitogen-activated protein kinase 10 is an enzyme that in humans is encoded by the MAPK10 gene.-Interactions:MAPK10 has been shown to interact with MAPK8IP3.-Further reading:...
(two isoforms). Each gene is expressed as either 46 kDa or 55 kDa protein kinases, depending upon how the 3' coding region of the corresponding mRNA is processed. There have been no functional differences documented between the 46 kDa and the 55 kDa isoform, however, a second form of alternative splicing occurs within transcripts of JNK1 and JNK2, yielding JNK1-α, JNK2-α and JNK1-β and JNK2-β. Differences in interactions with protein substrates arise because of the mutually exclusive utilization of two exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s within the kinase domain.
c-Jun N-terminal kinase isoforms have the following tissue distribution:
- JNK1MAPK8Mitogen-activated protein kinase 8 is an enzyme that in humans is encoded by the MAPK8 gene.-Interactions:MAPK8 has been shown to interact with SPIB, DUSP1, Activating transcription factor 2, SH3BP5, GSTP1, MAPK8IP1, MAP2K7, CRK, MAP2K4, DUSP22, Myc, MAP3K2, DUSP10, REL, MAPK8IP3, IRS1, MAP3K1 and...
and JNK2Mitogen-activated protein kinase 9Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.-Interactions:Mitogen-activated protein kinase 9 has been shown to interact with TOB1, Grb2, MAPK8IP2, P53, MAPK8IP3 and MAPK8IP1.-Further reading:...
are found in all cells and tissues. - JNK3MAPK10Mitogen-activated protein kinase 10 is an enzyme that in humans is encoded by the MAPK10 gene.-Interactions:MAPK10 has been shown to interact with MAPK8IP3.-Further reading:...
is found mainly in the brain, but is also found in the heart and the testes.
Function
Inflammatory signals, changes in levels of reactive oxygen species, ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. One way this activation may occur is through disruption of the conformation of sensitive protein phosphatase enzymes; specific phosphatases normally inhibit the activity of JNK itself and the activity of proteins linked to JNK activation.JNKs can associate with scaffold protein
Scaffold protein
In biology, scaffold proteins are crucial regulators of many key signaling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signaling pathway, tethering them into complexes...
s JNK interacting proteins as well as their upstream kinases JNKK1
MAP2K4
Dual specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.-Interactions:MAP2K4 has been shown to interact with FLNC, MAPK8, MAPK8IP3 and AKT1.-Further reading:...
and JNKK2
MAP2K7
Mitogen-activated protein kinase kinase 7, also known as MAP2K7, is ahuman gene.-Interactions:MAP2K7 has been shown to interact with GADD45B, MAPK8, MAPK8IP3, MAPK8IP1, MAP3K12, MAP3K2, MAPK8IP2 and DUSP19.-Further reading:...
following their activation.
JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Downstream molecules that are activated by JNK include c-Jun
C-jun
c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...
, ATF2
Activating transcription factor 2
Activating transcription factor 2, also known as ATF2, is a protein that, in humans, is encoded by the ATF2 gene.-Function:This gene encodes a transcription factor that is a member of the leucine zipper family of DNA-binding proteins. This protein binds to the cAMP-responsive element , an octameric...
, ELK1
ELK1
E twenty-six -like transcription factor 1, also known as Elk1, functions as a transcription activator. It is classified as a ternary complex factor , a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences...
, SMAD4
Mothers against decapentaplegic homolog 4
SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily...
, p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and HSF1
HSF1
Heat shock factor protein 1 is a protein that in humans is encoded by the HSF1 gene.-Function:The product of this gene is a heat-shock transcription factor. Transcription of heat-shock genes is rapidly induced after temperature stress...
. The downstream molecules that are inhibited by JNK activation include NFAT4
NFATC3
Nuclear factor of activated T-cells, cytoplasmic 3 is a protein that in humans is encoded by the NFATC3 gene.- External links :...
, NFATC1
NFATC1
Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the NFATC1 gene.-Further reading:- External links :...
and STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
. By activating and inhibiting other small molecules in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis.
JNK1 is involved in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
, cell differentiation and proliferation, inflammatory conditions and cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
production mediated by AP-1 (activation protein 1) such as RANTES
RANTES
Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. It is also known as RANTES .- Function :...
, IL-8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
and GM-CSF.
Recently, JNK1 has been found to regulate Jun
C-jun
c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...
protein turnover
Protein turnover
Protein turnover is the balance between protein synthesis and protein degradation. More synthesis than breakdown indicates an anabolic state that builds lean tissues, more breakdown than synthesis indicates a catabolic state that burns lean tissues....
by phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and activation of the ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
Itch
ITCH (biology)
ITCH is an ubiquitin-conjugating enzyme....
.
External links
- Getting a Handle on Cellular JNK (from Beaker Blog)
- MAP Kinase Resource