STEP, PTPRR, VHR, <extracellular region> Ca('2+) = <cytosol> Ca('2+), PKA-cat (cAMP-dependent), PTPR-epsilon, MKP-4, NMDA receptor, VRK3, JNK(MAPK8-10), ERK1/2, PKC, PKA-reg (cAMP-dependent), ZAP70, MKP-2, PP2A catalytic, ERK2 (MAPK1), Lck, MEK1(MAP2K1), MKP-7, MKP-X, AKT, MKP-3, MKP-1, PEA15, CD3, Calcineurin A (catalytic), Ca(2+) cytosol, Ca(2+) extracellular region, TCR alpha/beta, GMF, HePTP, CaMK II, Calmodulin
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 Ca(2+)/ Calmodulin -dependent 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-2, MKP-3, MKP-4, MKP-7 and MKP-X ) dephosphorylate both phosphotyrosine and phosphothreonine residues on ERK1/2 , , . Regulation of MKP activity includes ERK1/2 -dependent feedback 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 .