Disease relevance of EIF2AK3

• Using recombinant PEK produced in Escherichia coli or Sf-9 insect cells, we demonstrate that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2alpha on serine-51 [1].
• Pancreata of Perk(-/-) mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells [2].
• RCGP WRS may give the most reliable prevalence figures for musculoskeletal and other chronic diseases [3].

High impact information on EIF2AK3

• Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR [4].
• This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis [4].
• Northern blot analyses indicate that PEK mRNA is expressed in all tissues examined, with highest levels in pancreas cells [1].
• The addition of recombinant PEK to reticulocyte lysates caused a dose-dependent inhibition of translation [1].
• In addition to a catalytic domain with sequence and structural features conserved among eIF-2alpha kinases, PEK contains a distinctive amino-terminal region 550 residues in length [1].

Biological context of EIF2AK3

• Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity [5].
• Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans, and we suggest EIF2AK3 as a possible target for therapeutic intervention in diabetes [6].
• Assignment of pancreatic eIF-2alpha kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization [7].
• Phosphorylation of eukaryotic initiation factor-2 (eIF2) by pancreatic eIF2 kinase (PEK), induces a program of translational expression in response to accumulation of malfolded protein in the endoplasmic reticulum (ER) [8].
• These results suggest that this ER chaperone serves as a repressor of PEK activity, and release of ER chaperones from PEK when misfolded proteins accumulate in the ER induces gene expression required to enhance the protein folding capacity of the ER [8].

Anatomical context of EIF2AK3

• PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis [9].
• Consistent with our mRNA assays, PEK activity was predominantly detected in pancreas and pancreatic islet cells [1].
• Thus PEK is believed to play an important role in regulating protein synthesis in the pancreatic islet, especially in islet delta cells [10].
• After an adaptation period of 15 minutes, digital pressure was applied to the anterior perineum by one of the authors (WRS) [11].

Associations of EIF2AK3 with chemical compounds

• Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense serine 877 proline mutation [6].
• We describe the characterization of two regions in the ER luminal portion of the transmembrane PEK that carry out distinct functions in the regulation of this eIF2 kinase [8].
• The international review board was set up as the scientific advisory body of the Swiss Complementary Medicine Evaluation Programme (PEK) in 2002 [12].
• The use of bethanechol during RT for HNC cancer was associated with significantly higher WRS immediately after RT (p=0.03) in comparison to a similar cohort of patients who had not received bethanechol [13].

Regulatory relationships of EIF2AK3

• We show that human PEK is regulated by different mechanisms than PKR or HRI [10].

Other interactions of EIF2AK3

• ER luminal sequences flanking the transmembrane domain are required for GRP78 interaction, and deletion of this portion of PEK led to its activation even in the absence of ER stress [8].
• Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations [14].

Analytical, diagnostic and therapeutic context of EIF2AK3

• We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families [15].
• Results of the Prospective Evaluation of Radial Keratotomy (PERK) Study 4 years after surgery for myopia. Perk Study Group [16].
• These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs [4].
• Within the framework of the Swiss governmental Program of Evaluation of Complementary Medicine (PEK) we assessed the prevalence, use, perceived effectiveness and appreciation of complementary medicine (CAM) in Switzerland, according to published surveys [17].

References