Mitogen-activated protein kinase

Mitogen-activated protein kinase

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Mitogen-activated protein (MAP) kinases are serine/threonine-specific protein kinase
Serine/threonine-specific protein kinase
Serine/threonine protein kinases phosphorylate the OH group of serine or threonine .At least 125 of the 500+ human protein kinases are serine/threonine kinases .-Regulation:...

s that respond to extracellular stimuli (mitogen
Mitogen
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....

s, osmotic stress, heat shock
Heat shock
In biochemistry, heat shock is the effect of subjecting a cell to a higher temperature than that of the ideal body temperature of the organism from which the cell line was derived.-Heat shock response:...

 and proinflammatory cytokine
Proinflammatory cytokine
A proinflammatory cytokine is a cytokine which promotes systemic inflammation.Examples include IL-1 and TNF alpha....

s) and regulate various cellular activities, such as gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

, mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

, differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

, proliferation, and cell survival/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...

.

Activation


MAP kinases are activated within the protein kinase cascades called “MAPK cascade”. Each one consists of three enzymes, MAP kinase, MAP kinase kinase (MKK, MEK, or MAP2K) and MAP kinase kinase kinase (MKKK, MEKK or MAP3K) that are activated in series. A MAP3K that is activated by extracellular stimuli phosphorylates a MAP2K on its serine and threonine residues, and this MAP2K activates a MAP kinase through phosphorylation on its threonine and tyrosine residues (Tyr-185 and Thr-183 of ERK2). In vivo and in vitro, phosphorylation of 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...

 precedes phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other. Because both tyrosine and threonine phosphorylations are required to activate the MAP kinases, phosphatases that remove phosphate from either site will inactivate them.

The MAP kinase signaling cascades convey information to effectors, coordinate incoming information from other signaling pathways, amplify signals, and allow for a variety of response patterns. They respond to different stimuli by phosphorylating cytoplasmic components and nuclear transcription factors depending on the cellular context. Down-regulation of MAP kinase pathways may occur through dephosphorylation by serine/threonine phosphatases, tyrosine phosphatases, or dual-specificity phosphatases and through feedback inhibitory mechanisms that involve the phosphorylation of upstream kinases. Drugs that selectively down-regulate MAP kinase cascades could prove to be valuable as therapeutic agents in the control of malignant disease.

Groups


ERK1 and ERK2 were the first of the ERK/MAP kinase subfamily to be cloned. Other related mammalian enzymes have been detected including: two ERK3 isoforms, ERK4, Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38/HOG, and p57 MAP kinases (38). The presence of at least six MAP kinases in yeast suggests that there are more in mammals.
  1. extracellular signal-regulated kinases
    Extracellular signal-regulated kinases
    In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...

     (ERK1, ERK2). The ERK1/2 (also known as classical MAP kinases) signaling pathway is preferentially activated in response to growth factor
    Growth factor
    A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

    s and phorbol ester (a tumor promoter), and regulates cell proliferation and cell differentiation.
  2. c-Jun N-terminal kinases
    C-Jun N-terminal kinases
    c-Jun N-terminal kinases , were originally identified as kinases 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...

     (JNKs), (MAPK8
    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...

    , MAPK9, MAPK10
    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:...

    ) also known as stress-activated protein kinases (SAPKs).
  3. p38
    P38 mitogen-activated protein kinases
    P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....

     isoforms.(p38-α (MAPK14
    MAPK14
    Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.-Interactions:MAPK14 has been shown to interact with Casein kinase 2, alpha 1, RPS6KA4, MAPKAPK2, CDC25B, DUSP1, ZFP36L1, CDC25C, MAPKAPK3, Activating transcription factor 2, MAPK1,...

    ), -β (MAPK11
    MAPK11
    Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the MAPK11 gene.-Interactions:MAPK11 has been shown to interact with HDAC3 and Promyelocytic leukemia protein.-Further reading:...

    ), -γ (MAPK12
    MAPK12
    Mitogen-activated protein kinase 12 , also known as extracellular signal-regulated kinase 6 or stress-activated protein kinase 3 , is an enzyme that in humans is encoded by the MAPK12 gene.- Function :...

     or ERK6) and -δ (MAPK13
    MAPK13
    Mitogen-activated protein kinase 13 , also known as stress-activated protein kinase 4 , is an enzyme that in humans is encoded by the MAPK13 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...

     or SAPK4)) Both JNK
    C-Jun N-terminal kinases
    c-Jun N-terminal kinases , were originally identified as kinases 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...

     and p38
    P38 mitogen-activated protein kinases
    P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....

     signaling pathways 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, and are involved in cell differentiation and apoptosis.
  4. ERK5. ERK5 (MAPK7
    MAPK7
    Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.- Function :MAPK7 is a member of the MAP kinase family...

    ), which has been found recently, is activated both by growth factors and by stress stimuli, and it participates in cell proliferation.
  5. ERK3/4. ERK3 (MAPK6
    MAPK6
    Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the MAPK6 gene.-Further reading:...

    ) and ERK4 (MAPK4
    MAPK4
    Mitogen-activated protein kinase 4 is an enzyme that in humans is encoded by the MAPK4 gene.-Further reading:...

    ) are structurally-related atypical MAPKs possessing SEG motifs in the activation loop and displaying major differences only in the C-terminal extension. ERK3 and ERK4 are primarily cytoplasmic proteins that bind, translocate, and activate MK5 (PRAK, MAPKAP5). ERK3 is unstable, unlike ERK4, which is relatively stable.
  6. ERK7/8. (MAPK15
    MAPK15
    Mitogen-activated protein kinase 15 is an enzyme that in humans is encoded by the MAPK15 gene.-Further reading:...

    ) This is the newest member of MAPKs and behaves like atypical MAPKs. It possesses a long C terminus similar to ERK3/4.

Receptor tyrosine kinase


Various ligands that activate MAPK’s cascade bind receptor tyrosine kinases, and tyrosine residues are phosphorylated; the phosphotyrosine residues of autophosphorylated receptors then bind the SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...

s of adapters, (Grb2: growth factor receptor-bound protein 2). Exchange factors promote the association of Ras with GTP. GTP-Ras bind Raf-1 and B-Raf, two protein kinases. Consequently, Raf protein kinase activity is increased. Receptor tyrosine kinases have also been reported to activate the cascade in fibroblasts via a [Ca2+] increase.

G Protein-coupled receptors


The MAP kinase cascade can also be activated by certain heterotrimeric G proteins.

Protein kinase C


Protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...

 (PKC) is used by many receptors to regulate the MAP kinase pathway, alone or in concert with other mechanisms, and may act at several steps in the cascade. PKC may directly activate Raf-1, but if a mutation exists at the site phosphorylated by PKC, no interaction can occur with Raf. Other sites of action of PKC are likely to be either farther upstream or at the level of MAP kinase inactivation.

Regulation and specificity of MEKs


MEK1 and MEK2 phosphorylate and activate MAP kinase. MEKs are activated by Raf-1, B-Raf, the Mos protooncogene product, MEK kinase 1 (MEKK1), and other growth factor-stimulated activities. The mechanisms controlling MEKK1 are unknown, although Ras may be required. It is thought MEKs are kinases that phosphorylate only MAP Kinases because no other substrates have been identified.

3D Structure of MAPK1


The MAPK1
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...

 structure consists of a smaller N-terminal domain and a larger C-terminal domain connected by a linker.

If MAPK1 is unphosphorylated its activity is very low. Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 causes both global and local conformational changes. The two domains of ERK2 are rotated 17° to cause closure of the active site and form the catalytic residues. When Tyr-185 is phosphorylated binds Arg in positions -189 and −192. These new unions may help to stabilize the conformation in the active structure.

MAP kinase mutants and structural implications


Different biochemical and structural studies using mutations of the phosphorylation sites show how phosphorylation increases ERK2 activitiy. An example is that if the mutation is located in Tyr-185, it causes conformational changes that affect ERK2 activation and, so, the activity is lower. It is suggested that cells cannot tolerate the continuous activity of MAP kinase. Constitutively active mutants of MEK transform cells and generate tumors in nude mice. However, effects of activated MEKs could be compensated increasing phosphatase
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...

 activity to inactivate MAP kinases.

See also

  • MAPK/ERK pathway
    MAPK/ERK pathway
    The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...

  • MAPK1
    MAPK1
    Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...

     (ERK2)
  • MAPK3
    MAPK3
    Mitogen-activated protein kinase 3 is an enzyme that in humans is encoded by the MAPK3 gene.-Interactions:MAPK3 has been shown to interact with PTPN7, SPIB, GTF2I, DUSP3, HDAC4, RPS6KA2, MAP2K1, DUSP6 and MAP2K2.-Further reading:...

     (ERK1)
  • P38 MAPK
    P38 mitogen-activated protein kinases
    P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....

  • MAPK14
    MAPK14
    Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.-Interactions:MAPK14 has been shown to interact with Casein kinase 2, alpha 1, RPS6KA4, MAPKAPK2, CDC25B, DUSP1, ZFP36L1, CDC25C, MAPKAPK3, Activating transcription factor 2, MAPK1,...

     (p38-alpha)
  • Anthra(1,9-cd)pyrazol-6(2H)-one
    Anthra(1,9-cd)pyrazol-6(2H)-one
    1,9-Pyrazoloanthrone is a chemical compound that is a derivative of anthrone. It is used in biochemical studies as an inhbitor of c-Jun N-terminal kinases .Derivatives of 1,9-pyrazoloanthrone have a variety of biological activities...

     - inhibitor eg of JNK
  • Arc/Arg3.1
    Arc (protein)
    Arc, for activity-regulated cytoskeleton-associated protein , is a plasticity protein first characterized in 1995. Arc is a member of the immediate-early gene family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis...

    (acts via a MAPK cascade)

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