Last Updated: April 13, 2023
The MAP Kinase (MAPK) Cascades
The mitogen-activated protein (MAP) kinase (MAPK) family constitutes a large family of 13 genes that encode serine/threonine kinases that are involved in a wide range of signal transduction cascades. This large family of kinases has been organized into four distinct MAPK cascades named according to the MAPK component that is the central enzyme of each of the cascades. These four MAPK cascades are the extracellular signal-regulated kinase 1/2 (ERK1/2), the c-Jun N-terminal kinase (JNK), the p38, and the ERK5 cascades.
Each of these four cascades is in turn comprised of a core component that consists of three tiers of protein kinases termed MAPK, MAPKK, and MAP3K (MAPKKK). In several cases the cascade contains two additional tiers consisting of an upstream MAP4K and a downstream MAPKAPK (MAP kinase-activated protein kinase; MAPKAPK).
Signal transduction triggered by each cascade involves the sequential phosphorylation and activation of the components in the subsequent tiers. The MAPK signal transduction cascades involve the coordination of a variety of extracellular signals that are initiated to control diverse cellular processes such as proliferation, differentiation, survival, development, stress response, and apoptosis.
The ERK1/2 cascade primarily plays a role in proliferation and differentiation, however, there are situations where this cascade participates in responses to stress and apoptosis.
The JNK and p38 cascades are primarily activated in response to cellular stress, although the JNK kinases are known to mediate proliferation under certain conditions. Several of the components of the JNK and the p38 MAPK cascades are termed stress-activated protein kinases (SAPK).
The ERK5 cascade responds to both mitogenic signals and cellular stress signals.
The entirety of the MAPK systems involves nearly 70 individual genes which, due to alternative splicing events, generates a highly complex system of signaling molecules that includes over 200 proteins. Of clinical significance is that defective regulation of the MAPK cascades often leads to diseases such as cancer and diabetes.
The MAPK signaling cascades are most often initiated by receptor-mediated activation of members of the small monomeric G protein family, such as Ras, Rac, or Rho. In addition, the MAPK cascades can activate upstream components via their interactions with adaptor proteins. The initial signals are then propagated to downstream proteins of the three to five tiers of the four major MAPK cascades.
The kinases in each tier phosphorylate and activate the kinases located in the next tier downstream. This process is repeated from tier to tier allowing for rapid and regulated transmission of the original initiating signal. As indicated above, the MAPK, MAPKK and MAP3K tiers are core components of all MAPK cascades. The upstream (MAP4K) or the downstream (MAPKAPK) tiers are not always necessary for signaling through the MAPK cascades.
Table of Human MAP Kinase Family Proteins
| Protein Name | Gene Symbol | Other Names | Comments |
| mitogen-activated protein kinase-1 | MAPK1 | ERK, ERK2, p41mapk, MAPK2, ERT1, PRKM1, PRKM2 | located on chromosome 22q11.2; composed of 9 exons; generates two alternatively spliced mRNAs encoding the same 360 amino acid protein |
| mitogen-activated protein kinase-3 | MAPK3 | ERK1, p44mapk, p44ERK1, ERT2, PRKM3 | located on chromosome 16p11.2; composed of 10 exons; three alternatively spliced mRNAs encoding three isoforms; isoform 1 is a 379 amino acid protein, isoform 2 is a 357 amino acid protein, isoform 3 is a 335 amino acid protein |
| mitogen-activated protein kinase-4 | MAPK4 | ERK3-related, ERK4, PRKM4, p63MAPK | located on chromosome 18q21.1–q21.2; composed of 14 exons; three alternatively spliced mRNAs encoding three isoforms; isoform 1 is a 587 amino acid protein, isoform 2 is a 376 amino acid protein, isoform 3 is a 233 amino acid protein |
| mitogen-activated protein kinase-6 | MAPK6 | ERK3, p97MAPK, PRKM6 | located on chromosome 15q21.2; composed of 13 exons; encodes a 721 amino acid protein, protein is localized to the nucleus |
| mitogen-activated protein kinase-7 | MAPK7 | ERK4, ERK5, BMK1, PRKM7 | located on chromosome 17p11.2; composed of 9 exons; four alternatively spliced mRNAs, three of which encode the same protein; isoform 1 is a 816 amino acid protein; isoform 2 is a 677 amino acid protein |
| mitogen-activated protein kinase-8 | MAPK8 | JNK, JNK1, SAPK1, PRKM8 | located on chromosome 10q11.22; composed of 16 exons; 17 alternatively spliced mRNAs encoding six protein isoforms identified as α1, α2, β1, β2, 5, and 6 |
| mitogen-activated protein kinase-9 | MAPK9 | JNK2, JNK55, SAPK, PRKM9 | located on chromosome 5q35; composed of 18 exons; 13 alternatively spliced mRNAs encoding eight protein isoforms identified as α1, α2, β1, β2, γ, γ2, 11, and 12 |
| mitogen-activated protein kinase-10 | MAPK10 | JNK3, PRKM10, SAPK1b, p54bSAPK | located on chromosome 4q21.3; composed of 21 exons; nine alternatively spliced mRNAs encoding eight different isoforms identified as 1, 1x, 2, 3, 5, 6, 7, and 8; isoform 1 represents the dominant form of the MAPK10 encoded proteins; isoform 1x results from read-through of the UGA-stop codon utilized in the generation of isoform 1; isoform 6 initiates translation from an in-frame downstream start codon |
| mitogen-activated protein kinase-11 | MAPK11 | SAPK2, SAPK2B, p38β, PRKM11 | located on chromosome 22q13.33; composed of 13 exons: two alternatively spliced mRNAs only one of which encodes a protein of 364 amino acids, the other mRNA is a likely candidate for nonsense mediated mRNA decay |
| mitogen-activated protein kinase-12 | MAPK12 | ERK3, ERK6, SAPK3, PRKM12, p38γ | located on chromosome 22q13.33; composed of 12 exons; two alternatively spliced mRNAs; isoform 1 encodes a 367 amino acid protein, isoform 2 encodes a 357 amino acid protein; protein functions in the differentiation of myoblasts |
| mitogen-activated protein kinase-13 | MAPK13 | SAPK4, p38δ, PRKM13 | located on chromosome 6p21.31; composed of 12 exons; two alternatively spliced mRNAs; only one protein isoform is generated from transcription of the MAPK13 gene and is a 365 amino acid protein; the other mRNA is a likely candidate for nonsense mediated mRNA decay |
| mitogen-activated protein kinase-14 | MAPK14 | p38, PRKM14, PRKM15, SAPK2A, CSBP, EXIP, Mxi2 | located on chromosome 6p21.31; composed of 23 exons; four alternatively spliced mRNAs encoding four distinct protein isoforms |
| mitogen-activated protein kinase-15 | MAPK15 | ERK7, ERK8 | located on chromosome 8q24.3; composed of 14 exons encoding a 544 amino acid protein |
The ERK Cascade
The key proteins that comprise the ERK cascade are encoded by the MAPK1, MAPK3, MAPK4, and MAPK6. The proteins of the ERK cascade are activated by a variety of extracellular agents, such as growth factors and hormones, leading to the induction of, primarily, proliferation and differentiation. However, as pointed out above, some conditions such as cellular stress involve the ERK cascade.
The extracellular signals are relayed to the ERK cascade via the activation of GPCR, receptors with intrinsic tyrosine kinase activity (RTK), and ion channels. The extracellular signal transmission to ERK cascade kinases often involves adaptor proteins such as Shc or Grb2 (growth factor receptor-bound protein 2). These adapter proteins are recruited to the signaling receptor and then in turn activate guanine nucleotide exchange in membrane-bound monomeric G-proteins, such as Ras, rendering these G-proteins active. This in turn allows transmission of the signal to components of the MAP3K tier of the ERK cascade.
The primary MAP3K tier proteins are members of the Raf kinase family (Raf-1, A-Raf, B-Raf), but can also include tumor progression 1, TPL2 (formally called MAP3K8 but also known as MEKK8) and the stress-activated kinases MEKK1 and leucine zipper- and sterile alpha motif-containing kinase (ZAK; also called MLK-like mitogen-activated triple kinase: MLTK). Although MOS is another MAP3K of the ERK cascade, its primary function is in the reproductive system and has a distinct mode of regulation.
Subsequent to activation of proteins in the MAP3K tier, the signal is transmitted down the cascade to the MAPKK components. The proteins in this tier are called the MAPK/ERK kinases 1 and 2 (MEK1/2). The substrates for ERKs are regulatory proteins that includes one or more the MAPKAPK tier proteins. The MAPKAPK tier includes the ribosomal S6 kinase (RSK), the MAPK/SAPK-activated kinase (MSK), MAPK signal-interacting kinases 1 and 2 (MNK1/2), and MAPKAPK3/5. The important regulatory kinases, glycogen synthase kinase 3 (GSK3) and serine threonine kinase 11 (STK11; also called LKB1 or Peutz-Jeghers syndrome kinase: PJS) are known substrates for MAPKAPKs, but these latter kinases are not usually considered as integral components of the MAPK cascades.
The p38 Cascade
The key proteins that comprise the p38 cascade are encoded by the MAPK11, MAPK12, MAPK13, and MAPK14 genes. The p38 MAPK cascade is primarily functional when cells respond to various stressful stimuli but is also known to participate in immune responses and inflammation.
Activation of the p38 MAPK cascade occurs in response to various stress factors as well as ligands that activate GPCR, RTK, and apoptosis-related receptors. In addition to receptor-mediated activation of the p38 MAPK cascade, physical stresses such as osmotic shock or heat shock, strongly activate the cascade via receptor-independent processes that includes changes in membrane fluidity.
The primary inducing signals are then transmitted to monomeric G-proteins, similarly to the similar process of the ERK cascade, but involves other members of the monomeric G-protein family such as Rac. The subsequent steps in the p38 MAPK cascade involve activation of either the MAP4K tier or directly the MAP3K tier.
At least 20 distinct kinase encoding genes are known to express kinases that participate in the MAP3K tier of the p38 MAPK cascade. Additionally, many of these kinase genes express multiple splice variants leading to even more complexity to the MAP3K tier. The MAP3K components in the p38 MAPK cascade are many of the same kinases in the JNK cascade.
Characterizing the various p38 isoforms, based upon their differential sensitivity to various inhibitors and their unique sequences, allows them to be subdivided into two groups, p38α/p38β and p38γ/p38δ. Following their activation the p38 kinases then transmit their activation signals to the MAPKAPK tier components MAPKAPK2, MAPKAPK3, MNK1/2, MSK1/2, and MK5/PARK.
Alternatively, activated p38 kinases phosphorylate regulatory molecules such as PLA2, transcription factors such as ATF2, ELK1, CHOP, MEF2C, and various heat shock proteins. The p38 kinases can undergo bidirectional redistribution between the nucleus and cytosol upon their activation. Similar to the processes by which the ERK cascade activated MAPKAPK can phosphorylate additional kinases such as STK11, so too can the p38-activated MAPKAPK.
The JNK Cascade
The key proteins that comprise the JNK cascade are encoded by the MAPK8, MAPK9, and MAPK10 genes. Like the p38 MAPK cascade, the JNK cascade plays an important role in the response to cellular stress by inducing apoptosis. Given the similarities in activation triggers between the JNK and p38 cascades, it is apparent that the JNK cascade is responsive to the activation of stress/apoptosis-related receptors, GPCR, RTK, and receptor-independent physical stresses.
Following activation of the JNK kinases they transmit their signals to adapter that in turn activate the kinases in the MAP4K tier, and on occasion the MAP3K tier, of the JNK cascade. An additional activation scheme of the JNK cascade involves a network of interacting proteins that either induces changes in the activity of adapter proteins, such as members of the TRAF (TNF receptor-associated factor) family, or the activation of monomeric G-proteins such as Rac. Both of these activation processes then transmits the signal by activating MAP4K tier kinases, or sometimes directly activating MAP3K tier kinases.
The kinases in the MAP4K tier of the JNK cascade includes MAP4K2 (also called germinal center kinase, GCK), MAP4K3 (also called germinal center-like kinase, GLK), MAP4K1 (also called hematopoietic progenitor kinase 1, HPK1), and other Sterile 20-like (Ste20-like) kinases. Each of these can, in turn phosphorylate and activate kinases in the MAP3K tier. Most of the MAP3K tier kinases of the JNK cascade are the same as those in the p38 MAPK cascade. However, several other MAP3K tier kinase are unique to the JNK cascade such as ASK2, LZK1, MLK1, and MEKK4.
Following activation of the MAP3K kinases the signal is transmitted to kinases at the MAPKK level which are primarily MKK4 and MKK7 but may also include MKK3/6. The principal terminal proteins of the JNK cascade are the JNK proteins themselves. A total of 17 JNK proteins are translated from the three different JNK genes that undergo alternative splicing. The JNK cascade is a major regulator of transcription and involves migration of the JNK proteins to the nucleus where they interact with and activate transcription factor targets such as c-Jun, ATF2, and ELK1.
The ERK5 (MAPK7) Cascade
The fourth MAPK cascade was originally identified as the ERK5 cascade. This cascade comprises the protein isoforms encoded by the alternatively spliced mRNAs generated from the MAPK7 gene. This cascade is the least studied of the four. The ERK5 cascade was originally identified as being activated in response to stress stimuli, such as oxidative stress and hyperosmolarity, but was subsequently shown to also be activated mitogens.
Activation of this cascade can include protein Y-kinases that transmit their signals to the adapter proteins Lad1 or WNK1 (protein kinase, leucine deficient 1). These adapter proteins appear to play the role of the MAP4K tier in this cascade. These adapters then activate the MAP3K kinases MEKK2/3, as well as ZAK and TPL2.
The MAP3K tier kinases of the ERK5 cascade then phosphorylate and activate the two alternatively spliced MAPKK isoforms MEK5a and MEK5b. The MEK5s then phosphorylate and activate MAPK7 proteins. MAPK7 proteins can be localized to the cytoplasm and be translocated to the nucleus upon stimulation. However, in some cells MAPK7 proteins reside in the nucleus where they are activated by nuclear MEK5.
Several transcription factors, such as FOS, MYC, and MEF2 family members, are targets for activated MAPK7 proteins. Additionally, activated MAPK7 proteins can phosphorylate the serum and glucocorticoid-activated kinase (SGK), which may serve as a MAPKAPK of ERK5 cascade. Unique to this cascade is the fact that MAPK7 proteins can influence transcription through either direct protein–protein interactions or via its intrinsic transcriptional activity. Thus, MAPK7 proteins are unique dual activity proteins that, unlike other MAPK, catalyze two independent activities.
MAPK Regulation
Regulation and specificity of the four MAPK cascades is complex given that the consensus phosphorylation sites and the protein–protein interaction domains are shared by all MAPK. Adding to this regulatory complexity is the fact that the MAPKs induce phosphorylation of a large number of proteins. Indeed, ERK1/2 has been shown to have at least 160 different substrates and the number of substrates for p38 and JNK kinases is likely to be similarly high. Adding to regulatory complexity is the fact that the distinct MAPK cascades utilize proteins that are shared between the MAP4K and MAP3K tiers of the four cascades. Five mechanisms for determination of MAPK specificity have been proposed. These include pathway specific strength and duration of the signals; interaction with various scaffold proteins that control the localization of MAPK kinases to distinct components and substrates of the cascade; interactions between the various MAPK cascades or interactions with other signaling pathways; compartmentalization of components and their targets to subcellular regions of organelles; the presence of multiple components with distinct specificities in each level of a given cascade.
MAP Kinase Phosphatases
Given that the activity of the various MAP kinases is regulated by their being phosphorylated it is clear that dephosphorylation is a vital process in the overall control of MAP kinase activity. Phosphorylation of MAP kinases occurs on threonine or tyrosine residues and so dephosphorylation involves both protein serine/threonine phosphatases (PSP) and protein tyrosine phosphatases (PTP). Another family of MAP kinase phosphatases exhibit dual specificity being able to dephosphorylate both phosphothreonine and phosphotyrosine. This class of dual-specificity phosphatases (DUSP) has also been designated as MAP kinase phosphatases (MKP).
Humans express 11 genes encoding MAP kinase phosphatases which are members of the dual specificity phosphatase (DUSP) family, including DUSP1 (MKP-1), DUSP2, DUSP4 (MKP-2), DUSP5, DUSP6 (MKP-3), DUSP7, DUSP8, DUSP9 (MKP-4), DUSP10 (MKP-5), DUSP16 (MKP-7), and STYXL1 (serine/threonine/tyrosine interacting like 1; also identified as DUSP24). Based upon structural differences the DUSP proteins are divided into three subgroups. Group I includes DUSP1, 2, 4, and 5. Group II includes DUSP6, 7, 9, and 10. Group III includes DUSP8 and DUSP16. All DUSP possess a MAP kinase docking domain at the amino terminus, CDC25 homology (CH2) domains in the central portion of the proteins, and a C-terminally localized catalytic domain.
The DUSP1, 2, 4, and 5 encoded enzymes are localized to the nucleus. The DUSP6, 7, and 9 encoded enzymes are localized to the cytosol. The DUSP8, 10, and 16 encoded enzymes are localized to the nucleus and the cytosol. DUSP1 exhibits substrate specificity for JNK, p38, and ERK. DUSP2 exhibits substrate specificity for ERK and JNK. DUSP4 exhibits substrate specificity for ERK, JNK, and p38. DUSP5 exhibits substrate specificity for ERK. DUSP6 exhibits substrate specificity for ERK. DUSP7 exhibits substrate specificity for ERK. DUSP8 exhibits substrate specificity for JNK and p38. DUSP9 exhibits substrate specificity for ERK and p38. DUSP10 exhibits substrate specificity for JNK and p38. DUSP16 exhibits substrate specificity for JNK and p38.