title: Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP.
abstract: STEP (striatal-enriched phosphatase) is a non-receptor tyrosine phosphatase that is specifically expressed in the neurons of the central nervous system. STEP regulates the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs (mitogen-activated protein kinases), Src family kinases and NMDA (N-methyl-D-aspartic acid) receptors. The critical role of STEP in regulating these effectors requires that its activity be tightly regulated. Previous studies have demonstrated that the activity of STEP is regulated through reversible phosphorylation of a serine residue within the KIM (kinase-interacting motif), by cAMP-dependent PKA (protein kinase A). In the present paper we show that STEP is endogenously phosphorylated at two additional sites located within the KISs (kinase-specificity sequences). The basal activity of ERK (extracellular-signal-regulated kinase) and p38 MAPKs plays an important role in the phosphorylation of these two sites. Dephosphorylation of these two sites leads to polyubiquitination and proteolytic degradation of STEP. Conversely, the proteasome inhibitors MG-132 and epoxomicin can stabilize STEP. The active form of STEP is more susceptible to degradation than the inactive form. Taken together the results of the present paper establish that ubiquitin-dependent proteolysis could be a novel mechanism for irreversibly terminating the activity of STEP.
authors.affiliation: Department of Neurology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Saibal
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Ranjana
authors.initials: R
authors.lastname: Poddar
authors.forename: Ishani
authors.initials: I
authors.lastname: Deb
authors.forename: Surojit
authors.initials: S
authors.lastname: Paul
mesh_terms: D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002460:Cell Line; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D017434:Protein Structure, Tertiary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D048049:Extracellular Signal-Regulated MAP Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse