PERK
PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) or EIF2AK3 (eukaryotic translation initiation factor 2-alpha kinase 3), analogous with Ire1, is a serine/threonine transmembrane endoplasmic reticulum (ER) kinase. Established PERK substrates include the translation initiation factor eIF2α and the transcription factor Nrf2. PERK, Ire1 and ATF6 serve as a UPR control system in the ER to monitor cell homeostasis. Following stress, the UPR restores homeostasis via mechanisms that reduce ER protein load (eg. via RIDD, or eIF2α-mediated inhibition of translation), by increasing protein folding capacity (eg. transcriptional regulation of chaperones) and by activation of degradation pathways to remove unfolded proteins (ERAD, autophagy).
PERK activation triggers an analogous response wherein activation of PERK results in the specific loss of cyclin D1 through inhibition of cyclin D1 protein synthesis rather than any acceleration in protein degradation. This loss of cyclin D1 triggers cell cycle arrest in normal cells. PERK is one of at least 4 distinct eIF2α protein kinases which include the heme-regulated kinase (HRI) also known as EIF2AK1 kinase, the interferon-inducible, RNA-dependent protein kinase (PKR) known as EIF2AK2 kinase and GCN2 known as EIF2AK4. PERK can regulate cellular redox homeostasis through activation of Nrf2. PERK phosphorylates Nrf2 on threonine 80 located within the Neh2 domain of Nrf2. The ability of PERK to directly regulate FOXO and potentially override negative regulation by Akt supports a model wherein the UPR and ER stress have the capacity to finely tune signal output downstream of Akt. A more complete and detailed understanding of PERK downstream signaling is essential for developing such approaches.
References
1.Pytel D,et al. Oncogene. 2016;35(10):1207–1215.
PERK activation triggers an analogous response wherein activation of PERK results in the specific loss of cyclin D1 through inhibition of cyclin D1 protein synthesis rather than any acceleration in protein degradation. This loss of cyclin D1 triggers cell cycle arrest in normal cells. PERK is one of at least 4 distinct eIF2α protein kinases which include the heme-regulated kinase (HRI) also known as EIF2AK1 kinase, the interferon-inducible, RNA-dependent protein kinase (PKR) known as EIF2AK2 kinase and GCN2 known as EIF2AK4. PERK can regulate cellular redox homeostasis through activation of Nrf2. PERK phosphorylates Nrf2 on threonine 80 located within the Neh2 domain of Nrf2. The ability of PERK to directly regulate FOXO and potentially override negative regulation by Akt supports a model wherein the UPR and ER stress have the capacity to finely tune signal output downstream of Akt. A more complete and detailed understanding of PERK downstream signaling is essential for developing such approaches.
References
1.Pytel D,et al. Oncogene. 2016;35(10):1207–1215.
Apoptosis
PERK
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DNL343
产品货号 : M37220
cas no: 2278265-85-1
DNL343 是具有脑渗透性的激活真核起始因子 2B (eIF2B) 激活剂,可抑制异常整合应激反应 (ISR)。DNL343 可抑制中枢神经系统 (CNS) 的 ISR 活性,逆转神经变性和神经炎症。DNL343 还预防了 eIF2B 功能丧失 (LOF) 突变体突变小鼠的运动功能障碍和过早死亡。DNL343 在由 eIF2B LOF 和慢性 ISR 激活驱动的白质消失病 (VWMD) 研究中具有抑制潜力。 -
BAY 2965501
产品货号 : M36493
cas no: 2732902-08-6
BAY 2965501 是一种有效的选择性二酰基甘油激酶 zeta (DGKζ) 抑制剂。BAY 2965501 诱导 pERK 激活。BAY 2965501 可用于癌症的研究。 -
PERK-IN-6
产品货号 : M36418
cas no: 1337532-14-5
PERK-IN-6 (Compound 5) 是一种 PERK 抑制剂,IC50 为 2.5 nM。 -
GCN2-IN-7
产品货号 : M35733
cas no: 2396465-33-9
GCN2-IN-7 (compound 39) 是一种具有口服活性和选择性的 general control nonderepressible 2 (GCN2) 抑制剂 (IC50=5 nM),具有体内的抗肿瘤活性。 -
MK-28
产品货号 : M35599
cas no: 864388-65-8
MK-28 是有效、选择性的 PERK 激动剂。MK-28 在小鼠中表现出良好的药代动力学特征,且能透过血脑屏障。