[Cell Cycle 6:21, 2628-2632, 1 November 2007]; ©2007 Landes Bioscience

Perspective

Canonical and Alternative MAPK Signaling

Genaro Pimienta Abstract

Jaime Pascual*
Inflammation and Infectious Diseases Center; Burnham Institute for Medical
Research; La Jolla, California USA
*Correspondence to: Jaime Pascual; Inflammation and Infectious Diseases Center;
Burnham Institute for Medical Research; 10901 North Torrey Pines Road;La Jolla,
California 92037 USA; Tel: 858.646.3100; Fax: 858.646.3195; Email: pascual@
burnham.org
Original manuscript submitted: 08/17/07
Manuscript accepted: 08/22/07
Previously published online as a Cell Cycle E-publication:
http://www.landesbioscience.com/journals/cc/article/4930
The archetype of MAPK cascade activation is somewhat challenged by the most recent
discovery of unexpected phosphorylation patterns, alternative activation mechanisms and
sub-cellular localization, in various members of this protein kinase family. In particular,
activation by autophosphorylation pathways has now been described for the three best
understood MAPK subgroups: ERK1/2, JNK1/2 and p38α/β. Also, a form of dosage
compensation between homologs has been shown to occur in the case of ERK1/2 and
JNK1/2. In this paper we summarize the MAPK activation pathway, with an emphasis
on non-canonical examples. We use this information to propose a model for MAPK signal
transduction that considers a cross-talk between MAPKs with different activation loop
sequence motifs and unique C-terminal extensions. We highlight the occurrence of non-
canonical substrate specificity during MAPK auto-activation, in strong connection with
MAPK homo- and hetero-dimerization events.

Key words
kinase, autophosphorylation, dimerization,
activation loop, isoform
Introduction
Currently, much is known about the mitogen activated protein kinases (MAPKs) and
several comprehensive, by now classic (reviewed in refs. 1 and 2). We do not intend in this
paper to review the field as it has already been done copiously. We rather aim at recapitu-
lating what is known about MAPK signaling in connection with a series of new findings
that suggest the existence of non-canonical MAPK signaling events. We will therefore refer
to the key existing reviews when dealing with the general aspects of MAPK biology, and
give specific references only when discussing the new findings.

The MAPK Signaling Module

The MAPKs are a family of intracellular protein kinases, whose activity is regulated by
the phosphorylation of their activation loop on a conserved T and Y residues.1,2 Upon
stimulation by growth factors, inflammatory cytokines or physical stress, MAPKs get
activated by one or two upstream MAPK kinases (MKKs), all of which have S‑/T‑ and
Y‑dual‑specificity. The MAPK signaling cascade is modular because it comprises three
subsequent phosphorylation events (Fig. 1). This means that each MAPK is phosphory-
lated by one or two upstream dual‑specificity (S/T and Y) MKKs, which in turn are
activated by a large number of upstream S/T MKK kinases (MAP3Ks).1,2
The MAP3K‑MKK‑MAPK module is well conserved in all eukaryotes, from yeast to
humans.3 To function properly, this pipeline of protein kinases is held together and local-
ized inside the cell to particular sub‑cellular sites, by means of macromolecular scaffolds.4
These scaffolds are repeat‑motif extended proteins capable of interacting with multiple
protein substrates simultaneously.5 Their functional role is to bring together a particular
subgroup of MAPKs, with their upstream activators, their corresponding protein substrates
and ultimately, their inactivating protein phosphatases (MKPs)4 (Fig. 1). It is now clear
that the signal output relayed by an active MAPK is in part determined by its sub‑cellular
localization. Such localization can be cytoplasmic, to a particular microtubule‑associated
protein network, or to the nucleus, where gene expression takes place.6 Typical MAPK
substrates are nuclear transcription factors, cytoplasmic translation initiation factors and
apoptotic modulators of the Bcl‑2 family in the mitochondria.1,2

2628 Cell Cycle 2007; Vol. 6 Issue 21

 Canonical and Alternative MAPK signaling
Figure 1. Canonical and alternative MAPK activation. The minimal composi-
tion of a MAPK signaling cascade comprises three sequentially‑activated
protein kinases. This refers to the MAP3K(pink)‑MKK(red)‑MAPK(magenta)
signaling module. A MAPK signal starts at a membrane (green) and is trans-
duced intracellularly by the MAPK module through three stepwise phosphory-
lation events. Active MAPKs redistribute in the cell where they phosphorylate
their substrates (blue), modulating their activity. The specificity and temporal
integration of MAPK cascades is given by macromolecular scaffolds (purple)
that hold the different components together, regulating their interactions
and/or enzyme activity. Under certain circumstances, MAPKs phosphorylate
their scaffolds engaging in positive or negative feedback loops. An emerg-
ing concept is the notion of noncanonical MAPK activation pathways. In this
case, the MAPKs are activated by autophosphorylation (cyan), in a way that
is MKK‑independent. Most phosphorylation reactions happening along a
MAPK cascade are on S/T‑P motifs. The only exceptions are the activation
of MAPKs by MKK on a Y residue (orange) and the noncanonical cases in
which MAPKs autophosphorylate in sequences that are not only T‑P, but also
T‑G or T‑E motifs (cyan).
The MAPK Family of Proteins
There are at least five distinct MAPK subgroups each containing
several protein homologs. Each gene coding for a MAPK homolog
is in many cases differentially spliced, expanding every MAPK
subgroup to a collection of protein variants.
These five MAPK subgroups are: the extracellular signal‑regulated
kinases protein homologs 1 and 2 (ERK1/2); the big MAPK‑1
(BMK‑1), also referred to as ERK5; the stress‑activated protein
kinases‑1 (SAPK‑1), better known as the c‑Jun N‑terminal Kinase
homologs 1, 2 and 3 (JNK1/2/3); the (SAPK‑2) homologs: a, b and
d (p38a/b/d); and finally ERK6, also known as p38g.1,2
Two other subgroups are subject of debate, ERK3/4 and ERK7/8,
and will not be discussed in this paper. Also, we will only comment
on ERK1/2, JNK1/2 and p38a/b because these are the best
understood MAPKs.
The Structural Characteristics of MAPKs
MAPKs share a common structural topology that is a deriva-
tion of the typical protein kinase fold, first described in the crystal
structure of the protein kinase A (PKA).7 The protein kinase fold
can be dissected in two globular lobes, a small N‑terminal one,
mainly composed of b‑strands and a large C‑terminal lobe that is
www.landesbioscience.com Cell Cycle 2629
predominantly a‑helical. Based on the crystal structures of both inac-
tive and active/phosphorylated forms of the MAPKs, it is thought
that, upon phosphorylation of the T‑x‑Y loop, MAPKs undergo a
conformational arrangement of the N‑ and C‑terminal lobes, in
a way that the catalytic cleft can attain optimal kinase activity.1
The MAPKs interact with their upstream activators (MKKs), with
specific macromolecular scaffolds, with inactivating phosphatases
(MKPs), and with their substrates via well conserved docking sites.
The best characterized docking site is the so‑called docking groove,
located on the convex side of the MAPK globular structure.8 Two
features make MAPKs different from other protein kinases. First, the
MAPK insert is a distinctive structural segment of the MAPK family,
when compared with PKA and other protein kinases. This is a flex-
ible extension of about 50 amino acids, located in the C‑terminal
lobe.9,10 Second, a disordered region of variable length and amino
acid composition present in some isoforms in each MAPK subgroup
that extends at the end of the C‑terminal lobe. The functional role
of the MAPK‑insert and the C‑terminal extension is not well under-
stood yet. But based on hydrogen exchange mass spectrometry, it has
been presumed that they represent protein‑binding interfaces.11
Activation and Inactivation of MAPKs
MAPKs acquire physiologically relevant kinase activity only upon
dual phosphorylation of their conserved activation loop.12,13 This
motif is part of a flexible peptide extension (20–35 amino acids
long), referred to as the activation segment, in the C‑terminal lobe
of protein kinases.14 MAPKs have in their activation segment the
signature sequence T‑x‑Y, where x is E in the case of ERKs, P in the
case of JNKs, and G in the case of p38 homologs (Fig. 1).1,2
As it is typical of eukaryotic signal cascades, the activation
life‑time of the MAPK module is transient. After a stint of activation,
and once their functional role has been achieved, their T‑x‑Y loop is
dephosphorylated and the MAPK signal terminated.12
Regardless of the MKK homolog or the type of MKP acting to
activate or inactivate respectively a certain subgroup of MAPKs, the
reaction mechanism is thought to be a two‑step bimolecular colli-
sion, in which a given MKK or MKP molecule binds to a MAPK
protein and phosphorylates or dephosphorylates one of the two
phosphosites on the T‑x‑Y loop at a time.13 This makes the exis-
tence in vivo, of mono‑phosphorylated MAPK intermediates rather
obvious. In accordance, the mono‑phosphorylated forms of ERK1/2
have been observed in vivo15 and it has been proposed that ERK1/2
mono‑Tyrosine phosphorylated specie binds to the Golgi structure
during mitosis.16 A similar case refers to ERK1c that is a spliced
isoform of ERK1 with a unique C‑terminus. ERK1c localizes to the
Golgi during mitosis, where it is preferentially mono‑phosphorylated
by MEK1 on the tyrosine of its activated loop.17 Both (pY)‑ERK2
and (pY)‑ERK1c are thought to modulate the structure of the
mitotic Golgi vesicles.16,17
Despite their pervasiveness, a functional role (activation/
inactivation) has long been disregarded for these mono‑phosphory-
lated MAPK intermediates. Especially because it is widely accepted
that fully active MAPKs must be dual‑phosphorylated on the T‑x‑Y
motif. For some MAPKs, the inactive form has been attributed a
functional role. Such is the case of inactive JNK2 that in basal cellular
conditions binds to the transcription factors ATF2, c‑Jun and p53,
promoting their proteasomal degradation.18
 Canonical and Alternative MAPK signaling
A plausible assumption to make is that the inactive loop, either
non- or mono‑phosphorylated has different substrate affinities
than the fully phosphorylated MAPK and thus, may interact with
different pathway protein components. The crystal structures of non-
and dual‑phosphorylated ERK2 support this assumption. In this case
active ERK2 forms a stable dimer, promoted by the rearrangement of
the fully phosphorylated activation loop that provides a major part
of the dimer interface.10,19 The activated pT‑E‑pY loop in ERK also
promotes the detachment of ERK2 from its cytoplasmic scaffolds.20
A consequence is that inactive ERK2 is monomeric and cytoplasmic,
whereas active ERK2 forms stable dimmers and it is prompted to
translocate to the nucleus.19 As for the amino acid residues immedi-
ately flanking the T‑E‑Y loop in ERK2, it has been established, that
they have an important role in setting the phosphorylation/dephos-
phorylation ratio of ERK2, probably because these residues influence
the interaction of ERK2 with its upstream MKKs and MKPs.21
Overall, this means that the particular sequence of the activation
segment in each MAPK, together with the corresponding MKK and
MKP kinetic constants and their cellular distribution, is most prob-
ably a key determinant of the shape of the kinetic response curve in
each MAPK signaling cascade.
Alternative MAPK Activation Pathways
MAPKs are P‑directed protein kinases because they phosphorylate
their protein substrates on S or T that are N‑terminal to a P residue
(S/T‑P motifs).2 For this reason, it was expected a priori that JNKs
having a T‑P‑Y sequence signature would have autophosphorylation
properties,22 a postulate that has been verified in vitro and in vivo by
us and others.23,24 In the case of other MAPK subgroups that lack a
P residue in their activation loop (i.e., ERKs and p38 homologs), the
paradigm of MAPK S/T‑P substrate‑specificity has been challenged.
In particular with the finding of MAPK activation mechanisms that
are MKK‑independent because they originate from autophosphory-
lation reactions.
We summarize below the most relevant examples of MAPK auto-
phosphorylation and/or alternative activation pathways that we find
in the literature.
ERK1/2
Some of the first papers describing the mammalian ERK protein
homologs 1/2 reported basal S/T and Y autophosphorylation
activity for these protein kinases.25 It was also soon observed that
the activation segment of ERK1/2 is longer than the one present
in p38a/b or JNK1/2. Conversion of the activation segment in
p38a/b to a longer ERK‑like one, promotes its autophosphoryla-
tion,26 hinting at the unique ERK activation segment as a factor
causing its observed autophosphorylation.
The phosphorylation pattern of ERK2 has been investigated by
tandem mass spectrometry. It was shown that both in basal conditions
and upon stimulation by growth factors, a stoichiometric fraction of
total ERK is monophosphorylated on both the T and Y of the T‑E‑Y
motif.27 These findings may underpin the role of phospho‑Y ERK2
and ERK1c in the Golgi membranes as mentioned above.
2630 Cell Cycle 2007; Vol. 6 Issue 21
p38a/b
Structural studies have recently elucidated that p38 autophos-
phorylation occurs in trans‑ and that it is a consequence of protein
dimer interactions.28 In T‑cells, the activation and subsequent dimer-
ization of the T‑Cell antigen trans‑membrane receptor, leads to the
phosphorylation of the p38 homologs a and b on Y‑323, presumably
by the protein tyrosine kinase Zap70. This leads to the self‑activation
by autophosphorylation of p38a/b.29 Y‑323 is located in a region of
the catalytic domain that in the structure of active MAPKs corre-
sponds to the dimer interface.28
Autophosphorylation of p38a has also been observed as a func-
tion of the protein TAB1. In this case, there is no phosphorylation
event previous to p38 auto‑activation. TAB1 is thought to have a
non-enzymatic role in promoting p38 autophosphorylation, presum-
ably by forming a high molecular weight complex with p38a.30 It is
possible that TAB1, in analogy to Zap70, promotes the dimerization
of p38a/b, an event that leads to p38a autophosphorylation.
JNK1/2
JNK1/p46 is a short JNK homolog, and the main kinase activity
responsible of relaying most of the MAPK/JNKs cascades investi-
gated so far. It has been described that JNK1 can be phosphorylated
on S‑129 presumably by the basal activity of PKCd.31,32 The model
put forward is that in melanoma, the MAPK protein scaffold
RACK1 brings together the UV‑induced JNK1 signalosome (POSH
scaffold‑RACK1 scaffold‑MKK7‑JNK1‑substrates) and PKCd,
leading to a predisposition of JNK1 to be activated by upstream
MKK4/7.33 These findings have lead to the “Priming Hypothesis”,
which postulates that the presence of PKCd in basal conditions,
primes the activation of JNK1 upon UV‑activation.34
JNK2/p55, which is a JNK homolog with a C‑terminal exten-
sion, is up‑to‑date described to have a negligible or at least not yet
understood role as a kinase during most JNK signaling outputs,
despite its strong in vitro kinase activity.35 It has been reported that
JNK2 has basal kinase activity in glioma cells36 and autophosphory-
lation properties in vitro.23 Motivated by this information, we have
investigated and recently published the phosphorylation pattern of
inactive and active JNK2 obtained by tandem mass spectrometry.24
We find in our studies that JNK2 is a phospho‑protein already
in basal conditions with its activation loop mono‑phosphorylated
on the T, or the Y, and on a novel phosphosite, T‑386 outside the
catalytic domain. We also find that when activated by UV, JNK2
becomes a mixture of active JNK2 (dual‑phosphorylated) and the
aforementioned mono‑phosphorylated species, which dilute the net
intracellular concentration of the fully active JNK2. This “intracellular
dilution” of active JNK2 presumably promoted by its auto‑activation
properties may underpin the notion that JNK2 has “futile” role in
most JNK signaling cascades.35 In the case of pT‑386, located on
the unique C‑terminal site that makes JNK2 longer than JNK1, a
functional role has yet not been established.
Conclusions and Perspectives
Cells sense and respond to multiple stimuli, both transient
and prolonged. The integration of these signals starts at the basal
membrane and is orchestrated by various signaling cascades that relay
 Canonical and Alternative MAPK signaling

and a sustained activation of ERK2 in vivo.42 Finally, we find in the

literature that the activities of ERK1/2 and p38a/b cross‑talk in a
way that a high ERK/p38 activity ratio is in some cases prognostic
of tumor growth.43
To summarize, we suggest considering the MAPK family as a
pool of different protein homologs with specific hetero‑dimerization
and trans‑phosphorylation properties among them, as a function of
the different lengths in their activation segments and C‑terminal
appendages to the catalytic domain (Fig. 2). Our view encompasses
the different MAPK activation mechanisms (both generic and non-
canonical), the various activation/inactivation kinetics observed so
far for MAPKs, and the various inter‑MAPK dosage compensations
occurring in vivo.
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