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Signal transduction Erk Interactions: Inhibition of Erk

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Signal transduction Erk Interactions: Inhibition of Erk

Erk Interactions: Inhibition of Erk

Mitogen-activated protein kinase (MAPK) pathways regulate a variety of physiologicalprocesses, such as cell growth, differentiation, and apoptotic cell death. To date, threeMAPK 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-JunN-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 pathways arestimulated mainly by environmental stress and inflammatory cytokines. The ERK pathway,which includes the regulation and signaling cascade of Mitogen-activated protein kinases3 and 1 ( ERK1/2 ), is involved in cell growth, proliferation and survival [1].

Reversible phosphorylation of MAPK proteins emphasizes the importance of balancebetween the phosphorylating kinases and dephosphorylating phosphatases in regulatingthese pathways. In general, dephosphorylation of MAPKs decreases their kinase activitythat is essential for cell to remain responsive to stimuli and to prevent deleteriouseffects of prolonged pathway stimulation [1], [2].

ERK pathway phosphatases are classified according to their substrate specificitiesinto dual-specificity MAPK phosphatases, protein serine/threonine phosphatases, andprotein tyrosine phosphatases. In addition, two different families of phosphatases cancooperate in complex to regulate ERK1/2 dephosphorylation. A cholesterol-regulatedProtein phosphatase 2A ( PP2A catalytic )/ Protein tyrosine phosphatase,non-receptor type 7 ( HePTP ) complex dephosphorylates both the phosphotyrosineand the phosphothreonine residues in the activation loop of ERK1/2 due to thecombined activities of the serine/threonine phosphatase PP2A catalytic and thetyrosine phosphatase HePTP [3].

PP2A catalytic dephosphorylates and blocks activation of both ERK1/2 andits upstream kinase, Mitogen-activated protein kinase kinase 1 ( MEK1(MAP2K1) ),determining the kinetics of MAPK cascades [4], [5].

HePTP inactivates ERK1/2 by dephosphorylating the criticalphosphorylated tyrosine residue in their activation loop. Cyclic-AMP-dependent proteinkinase (composed of regulatory PKA-reg (cAMP-dependent) and catalytic PKA-cat(cAMP-dependent) subunits) phosphorylates HePTP reducing its binding toERK1/2 which causes ERK1/2 release and activation [6].

Protein tyrosine phosphatase receptor type ( RPTPRR ) and Protein tyrosinephosphatase non-receptor type 5 ( STEP ) retain ERK1/2 in the cytoplasm inan inactive form by association through a kinase interaction motif and tyrosinedephosphorylation. Phosphorylation of RPTPRR and STEP by PKA-cat(cAMP-dependent) suppresses their association with ERK1/2 and favorsERK1/2 activation and translocation to the nucleus [7], [8], [9].

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 thenucleus and its subsequent downstream nuclear signaling. NMDA-mediated influx ofCa(2+) leads to activation of the Ca(2+)/ Calmodulin -dependentphosphatase Calcineurin A (catalytic) that dephosphorylates and activatesSTEP [10].

Protein tyrosine phosphatase receptor type E ( PTPR-epsilon ) is also aphysiological inhibitor of ERK signaling by protecting cells from prolonged ERK1/2activation in the cytosol [11].

Glia maturation factor beta ( GMF ) is an inhibitor of ERK1/2, andphosphorylation of GMF by PKA-cat (cAMP-dependent) dramatically increasesits inhibitory effect [12].

Dual-specificity phosphatases (such as MKP-1, MKP-2, MKP-3,MKP-4, MKP-7 and MKP-X ) dephosphorylate both phosphotyrosine andphosphothreonine residues on ERK1/2 [13], [1], [2]. Regulation of MKP activity includes ERK1/2 -dependent feedbackmechanism for activation phosphatase function [14], [15], [1], [16]. For example, ERK1/2 can phosphorylate MKP-1and MKP-2 and prevent their degradation by inhibiting ubiquitination [17], [15].

MKP-1 and MKP-7 can also dephosphorylate and inactivateMitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ), changing the levels ofsignaling through multiple MAPK pathways [18], [19], [20], [21].

T cell receptor ( TCR alpha/beta )- CD3 complex also plays an importantrole in regulating ERK pathways in T cells. In TCR signaling, Zeta-chain (TCR) associatedprotein kinase 70kDa ( ZAP70 ) is phosphorylated and activated bylymphocyte-specific protein tyrosine kinase ( Lck ), leading to the activation ofERK pathway [22], [23], [24]. Dual specificityphosphatase 3 ( VHR ) accumulates at the T cell/ Antigen presenting cell (APC)contact site, where it is phosphorylated by ZAP70. This phosphorylation isrequired for VHR to inhibit ERK1/2, giving ZAP70 an unanticipatedcontrol over ERK signaling pathway, in addition to its role as upstream activator of theRas/Raf/MEK/ERK pathway [25], [26].

VHR is a constitutively expressed tyrosine-specific phosphatase whichspecifically dephosphorylates and inactivates ERK1/2 in the nucleus [27]. Vaccinia related kinase 3 ( VRK3 ) suppresses ERK1/2 activitythrough direct binding to VHR. VRK3 enhances the phosphatase activity ofVHR by a mechanism independent of its kinase activity, [28], [29].

ERK1/2 activity is also regulated by its subcellular localization, which can becontrolled by Phosphoprotein enriched in astrocytes 15 ( PEA-15 ). PEA-15directly binds to and sequesters ERK1/2 in the cytoplasm thereby preventingERK1/2 access to nuclear targets [30], [31], [32], [33]. Phosphorylation of PEA-15 byCalcium/calmodulin-dependent protein kinase II ( CaMK II ), Protein kinase C (PKC ) and v-Akt murine thymoma viral oncogene homolog ( AKT ) blocks itsinteraction with ERK1/2 and abrogates its capacity to prevent the nuclearlocalization of ERK1/2 [34].