Erk Interactions: Inhibition of Erk
Mitogen-activated protein kinase (MAPK) pathways regulate a variety of physiological
processes, such as cell growth, differentiation, and apoptotic cell death. To date, three
MAPK pathways have been characterized in detail. The extracellular regulated kinase (ERK)
pathway is activated by a large variety of mitogens and growth factors, whereas the c-Jun
N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 pathways are
stimulated mainly by environmental stress and inflammatory cytokines. The ERK pathway,
which includes the regulation and signaling cascade of Mitogen-activated protein kinases
3 and 1 (ERK1/2), is involved in cell growth, proliferation
and survival .
Reversible phosphorylation of MAPK proteins emphasizes the importance of balance
between the phosphorylating kinases and dephosphorylating phosphatases in regulating
these pathways. In general, dephosphorylation of MAPKs decreases their kinase activity
that is essential for cell to remain responsive to stimuli and to prevent deleterious
effects of prolonged pathway stimulation , .
ERK pathway phosphatases are classified according to their substrate specificities
into dual-specificity MAPK phosphatases, protein serine/threonine phosphatases, and
protein tyrosine phosphatases. In addition, two different families of phosphatases can
cooperate in complex to regulate ERK1/2 dephosphorylation. A
cholesterol-regulated Protein phosphatase 2A (PP2A
catalytic)/ Protein tyrosine phosphatase, non-receptor type 7
(HePTP) complex dephosphorylates both the phosphotyrosine
and the phosphothreonine residues in the activation loop of
ERK1/2 due to the combined activities of the
serine/threonine phosphatase PP2A catalytic and the tyrosine
phosphatase HePTP .
PP2A catalytic dephosphorylates and blocks activation of
both ERK1/2 and its upstream kinase, Mitogen-activated
protein kinase kinase 1 (MEK1(MAP2K1)), determining the
kinetics of MAPK cascades , .
HePTP inactivates ERK1/2 by
dephosphorylating the critical phosphorylated tyrosine residue in their activation loop.
Cyclic-AMP-dependent protein kinase (composed of regulatory PKA-reg
(cAMP-dependent) and catalytic PKA-cat (cAMP-dependent)
subunits) phosphorylates HePTP reducing its
binding to ERK1/2 which causes ERK1/2
release and activation .
Protein tyrosine phosphatase receptor type (RPTPRR) and
Protein tyrosine phosphatase non-receptor type 5 (STEP)
retain ERK1/2 in the cytoplasm in an inactive form by
association through a kinase interaction motif and tyrosine dephosphorylation.
Phosphorylation of RPTPRR and
STEP by PKA-cat (cAMP-dependent)
suppresses their association with ERK1/2 and
favors ERK1/2 activation and translocation to the nucleus
, , .
In neurons, activation of NMDA receptors leads to
activation of STEP, which limited the duration of
ERK1/2 activity as well as its translocation to the nucleus
and its subsequent downstream nuclear signaling. NMDA-mediated influx of
Ca(2+) leads to activation of the
phosphatase Calcineurin A (catalytic) that dephosphorylates
and activates STEP .
Protein tyrosine phosphatase receptor type E
(PTPR-epsilon) is also a physiological inhibitor of ERK
signaling by protecting cells from prolonged ERK1/2
activation in the cytosol .
Glia maturation factor beta (GMF) is an inhibitor of
ERK1/2, and phosphorylation of
GMF by PKA-cat (cAMP-dependent)
dramatically increases its inhibitory effect .
Dual-specificity phosphatases (such as MKP-1,
MKP-4, MKP-7 and
MKP-X) dephosphorylate both phosphotyrosine and
phosphothreonine residues on ERK1/2 , , . Regulation of MKP activity includes
mechanism for activation phosphatase function , , , . For example, ERK1/2 can
phosphorylate MKP-1 and MKP-2
and prevent their degradation by inhibiting ubiquitination , .
MKP-1 and MKP-7 can also
dephosphorylate and inactivate Mitogen-activated protein kinases 8-10
(JNK(MAPK8-10)), changing the levels of signaling through
multiple MAPK pathways , , , .
T cell receptor (TCR
alpha/beta)-CD3 complex also plays an
important role in regulating ERK pathways in T cells. In TCR
signaling, Zeta-chain (TCR) associated protein kinase 70kDa
(ZAP70) is phosphorylated and
activated by lymphocyte-specific protein tyrosine kinase
(Lck), leading to the activation of ERK pathway , , . Dual specificity phosphatase 3
(VHR) accumulates at the T cell/ Antigen presenting cell
(APC) contact site, where it is phosphorylated by ZAP70.
This phosphorylation is required for VHR to inhibit
ERK1/2, giving ZAP70 an
unanticipated control over ERK signaling pathway, in addition to its role as upstream
activator of the Ras/Raf/MEK/ERK pathway , .
VHR is a constitutively expressed tyrosine-specific
phosphatase which specifically dephosphorylates and inactivates
ERK1/2 in the nucleus . Vaccinia related
kinase 3 (VRK3) suppresses
ERK1/2 activity through direct binding to
VHR. VRK3 enhances the
phosphatase activity of VHR by a mechanism independent of
its kinase activity, , .
ERK1/2 activity is also regulated by its subcellular
localization, which can be controlled by Phosphoprotein enriched in astrocytes 15
(PEA-15). PEA-15 directly binds
to and sequesters ERK1/2 in the cytoplasm thereby preventing
ERK1/2 access to nuclear targets , , , . Phosphorylation of
PEA-15 by Calcium/calmodulin-dependent protein kinase II
(CaMK II), Protein kinase C
(PKC) and v-Akt murine thymoma viral oncogene homolog
(AKT) blocks its interaction with
ERK1/2 and abrogates its capacity to prevent the nuclear
localization of ERK1/2 .
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