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Impact of Redox Modification on ERK2 Global Substrate Selection
Başlık:
Impact of Redox Modification on ERK2 Global Substrate Selection
Yazar:
Postiglione, Anthony Earl, author.
ISBN:
9780355983821
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (61 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Robert H. Newman Committee members: Patrick M. Martin; Perpetua M. Muganda.
Özet:
Extracellular regulated kinase 2 (ERK2), which is the terminal serine/threonine protein kinase in the Ras-Raf-MEK-ERK signaling axis, is involved in the regulation of many cellular processes, including cell proliferation, differentiation, survival, and cell cycle progression. Recently, ERK2 was shown to undergo reversible oxidation on C159 following lysophosphatidic acid (LPA) treatment in SKOV3 ovarian cancer cells (Keyes et al., 2017). Interestingly, C159 is located within the D-recruitment site (DRS), which is involved in binding a subset of ERK2 substrates. Therefore, we compared the ability of wild-type ERK2 and ERK2(C159S) to phosphorylate a model DRS peptide substrate, Sub-D, following treatment with various concentrations of H2O2. These studies revealed a nearly two-fold difference between the observed IC 50 values for wild-type ERK2 and ERK2(C159S). Likewise, kinetic analysis demonstrated that while both wild-type ERK2 and ERK2(C159S) exhibit similar Km and kcat values in the absence of H2O2, treatment with H2O2 causes significant differences in both Km and k cat between these enzymes. Together, these data suggest that redox modification of ERK2 may alter its ability to phosphorylate substrates recognized by the DRS. This raised the intriguing possibility that oxidation could alter ERK2's activity toward some, but not all, of its downstream substrates. To explore this possibility further, we investigated the impact of redox modification on ERK2's global substrate selectivity using functional protein microarrays. Consistent with our hypothesis, ERK2-mediated phosphorylation of several substrates was unaffected by H2O2 treatment while others exhibited H2O2-dependent changes in their phosphorylation status. These findings suggest that redox modification of C159 may be used to modulate downstream substrate selection of ERK2 under certain physiological and pathological states.
Notlar:
School code: 1544
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(689624.1) | 689624-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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