Characterization of a Mutant Pancreatic eIF-2α Kinase, PEK, and Co-localization with Somatostatin in Islet Delta Cells

Abstract

Phosphorylation of eukaryotic translation initiation factor-2α (eIF-2α) is one of the key steps where protein synthesis is regulated in response to changes in environmental conditions. The phosphorylation is carried out in part by three distinct eIF-2α kinases including mammalian double-stranded RNA-dependent eIF-2α kinase (PKR) and heme-regulated inhibitor kinase (HRI), and yeast GCN2. We report the identification and characterization of a related kinase, PEK, which shares common features with other eIF-2α kinases including phosphorylation of eIF-2α in vitro. We show that human PEK is regulated by different mechanisms than PKR or HRI. In contrast to PKR or HRI, which are dependent on autophosphorylation for their kinase activity, a point mutation that replaced the conserved Lys-614 with an alanine completely abolished the eIF-2α kinase activity, whereas the mutant PEK was still autophosphorylated when expressed in Sf-9 cells. Northern blot analysis indicates that PEK mRNA was predominantly expressed in pancreas, though low expression was also present in several tissues. Consistent with the high levels of mRNA in pancreas, the PEK protein was only detected in human pancreatic islets, and the kinase co-localized with somatostatin, a pancreatic delta cell-specific hormone. Thus PEK is believed to play an important role in regulating protein synthesis in the pancreatic islet, especially in islet delta cells. Phosphorylation of eukaryotic translation initiation factor-2α (eIF-2α) is one of the key steps where protein synthesis is regulated in response to changes in environmental conditions. The phosphorylation is carried out in part by three distinct eIF-2α kinases including mammalian double-stranded RNA-dependent eIF-2α kinase (PKR) and heme-regulated inhibitor kinase (HRI), and yeast GCN2. We report the identification and characterization of a related kinase, PEK, which shares common features with other eIF-2α kinases including phosphorylation of eIF-2α in vitro. We show that human PEK is regulated by different mechanisms than PKR or HRI. In contrast to PKR or HRI, which are dependent on autophosphorylation for their kinase activity, a point mutation that replaced the conserved Lys-614 with an alanine completely abolished the eIF-2α kinase activity, whereas the mutant PEK was still autophosphorylated when expressed in Sf-9 cells. Northern blot analysis indicates that PEK mRNA was predominantly expressed in pancreas, though low expression was also present in several tissues. Consistent with the high levels of mRNA in pancreas, the PEK protein was only detected in human pancreatic islets, and the kinase co-localized with somatostatin, a pancreatic delta cell-specific hormone. Thus PEK is believed to play an important role in regulating protein synthesis in the pancreatic islet, especially in islet delta cells. eukaryotic protein synthesis initiation factor-2α subunit pancreatic eIF-2α kinase the double-stranded RNA-dependent eIF-2α kinase the hemeregulated inhibitor kinase the yeast general amino acid control eIF-2α kinase kilobase(s) polymerase chain reaction base pair(s) expressed sequence tag rapid amplification of cDNA ends It is generally accepted that protein biosynthesis in eukaryotes is controlled at the level of polypeptide chain initiation. Mammalian protein synthesis is promptly adjusted in response to a variety of different environmental stimuli including nutrient starvation, heat shock, and viral infection (1Mathews M.B. Sonenberg N. Hershey J.W.B. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 1-30Google Scholar). One of the best studied mechanisms of translational regulation involves the phosphorylation of the α-subunit of eukaryotic initiation factor-2 (eIF-2α)1 (2Clemens M.J. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 139-172Google Scholar, 3Wek R.C. Trends Biochem. Sci. 1994; 19: 491-496Abstract Full Text PDF PubMed Scopus (129) Google Scholar, 4Samuel C.E. J. Biol. Chem. 1993; 268: 7603-7606Abstract Full Text PDF PubMed Google Scholar, 5Hinnebusch A.G. Semin. Cell Biol. 1994; 5: 417-426Crossref PubMed Scopus (122) Google Scholar, 6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar). During translation initiation, eIF-2 catalyzes the binding of the initiator Met-tRNA to the 40 S ribosomal subunit by hydrolyzing GTP to GDP. eIF-2 is released from the ribosome as an inactive form bound to GDP in a binary complex (7Merrick W.C. Hershey J.W.B. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 31-70Google Scholar). To participate in the next round of translation initiation, the GDP-bound eIF-2 has to be converted to the active GTP bound form. This is carried out by the guanine nucleotide exchange factor eIF-2B, which is present at a lower molar concentration in the cell. Phosphorylation of eIF-2α results in inhibition of the eIF-2B activity, reducing the rate of nucleotide exchange, thus the rate of polypeptide chain initiation (7Merrick W.C. Hershey J.W.B. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 31-70Google Scholar). Eukaryotic protein synthesis is subject to regulation by various conditions where eIF-2α phosphorylation is in parallel with an inhibition of translation initiation (1Mathews M.B. Sonenberg N. Hershey J.W.B. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 1-30Google Scholar, 6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar). Three protein kinases have been studied in detail based on their ability to phosphorylate eIF-2α. These include the double-stranded RNA-dependent kinase (PKR) (8Meurs E. Chong K. Galabru J. Thomas N.S.B. Kerr I.M. Williams B.R.G. Hovanessian A.G. Cell. 1990; 62: 379-390Abstract Full Text PDF PubMed Scopus (816) Google Scholar, 9Thomis D.C. Doohan J.P. Samuel C.E. Virology. 1992; 188: 33-46Crossref PubMed Scopus (104) Google Scholar, 10Goodison S. Kenna S. Ashcroft S.J. Biochem. J. 1992; 285: 563-568Crossref PubMed Scopus (71) Google Scholar, 11Icely P.L. Gros P. Bergeron J.J. Devault A. Afar D.E. Bell J.C. J. Biol. Chem. 1991; 266: 16073-16077Abstract Full Text PDF PubMed Google Scholar, 12Feng G.S. Chong K. Kumar A. Williams B.R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5447-5451Crossref PubMed Scopus (155) Google Scholar, 13Mellor H. Flowers K.M. Kimball S.R. Jefferson L.S. Biochim. Biophys. Acta. 1994; 1219: 693-696Crossref PubMed Scopus (24) Google Scholar), heme-regulated inhibitor kinase (HRI) (14Chen J.J. Throop M.S. Gehrke L. Kuo I. Pal J.K. Brodsky M. London I.M. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 7729-7733Crossref PubMed Scopus (168) Google Scholar, 15Mellor H. Flowers K.M. Kimball S.R. Jefferson L.S. J. Biol. Chem. 1994; 269: 10201-10204Abstract Full Text PDF PubMed Google Scholar), and yeast and Drosophila GCN2 (16Roussou I. Thireos G. Hauge B.M. Mol. Cell. Biol. 1988; 8: 2132-2139Crossref PubMed Scopus (59) Google Scholar, 17Wek R.C. Jackson B.M. Hinnebusch A.G. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 4579-4583Crossref PubMed Scopus (203) Google Scholar, 18Santoyo J. Alcalde J. Mendez R. Pulido D. de Haro C. J. Biol. Chem. 1997; 272: 12544-12550Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 19Olsen D.S. Jordan B. Chen D. Wek R.C. Cavener D.R. Genetics. 1998; 149: 1495-1509Crossref PubMed Google Scholar). The kinases differ from other families of serine/threonine kinases by the presence of a large insert between domains III and V (20Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2280) Google Scholar). The eIF-2α kinases share extensive homology within the catalytic domains and each of the kinases has been demonstrated to phosphorylate eIF-2α specifically on the Ser-51 residue (2Clemens M.J. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 139-172Google Scholar, 5Hinnebusch A.G. Semin. Cell Biol. 1994; 5: 417-426Crossref PubMed Scopus (122) Google Scholar). In contrast, little homology is found in the regulatory domains of the kinases, which mediate response to different environmental stresses. The presence of distinct regulatory domains within each eIF-2α kinase allows for different physiological signals to regulate phosphorylation of eIF-2α. PKR is regulated by two double-stranded RNA binding motifs located in the N terminus of the protein (6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar). PKR is ubiquitously expressed in various tissues at very low levels, and expression can be induced by treatment with interferon or upon viral infection (21Samuel C.E. Kuhen K.L. George C.X. R. H. J. 1997; PubMed Google Scholar). The kinase has been to participate in the viral PKR can be by double-stranded RNA the of of PKR results in phosphorylation of eIF-2α and of protein and of the to cells. PKR has also been to play a role in regulating and Trends Biochem. Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, B.R. Biochem. 1997; PubMed Scopus Google Scholar). The kinase of is regulated by two regulatory which mediate the inhibition by J.J. London I.M. Trends Biochem. Sci. 1995; Full Text PDF PubMed Scopus Google Scholar). The kinase inhibition of protein synthesis in the of inhibition is inhibition is to to synthesis of the protein in the kinase is also present in the human large amino acid insert between kinase and V was in the kinase, which from the kinase J.J. B. B. Biochem. J. 1997; PubMed Scopus Google Scholar). In contrast to is predominantly expressed in a low level of mRNA is found in tissues H. Flowers K.M. Kimball S.R. Jefferson L.S. Biochim. Biophys. Acta. 1994; 1219: 693-696Crossref PubMed Scopus (24) Google Scholar), the kinase was in tissues by K. London I.M. Chen J.J. Mol. Cell. Biol. 1994; PubMed Google Scholar). In contrast to PKR and HRI, which are believed to regulate protein synthesis within a yeast GCN2 has been to specifically regulate expression of in response to amino acid A.G. J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar). is a factor that than in amino acid biosynthesis in of PKR and results in inhibition of translation initiation, phosphorylation of eIF-2α by GCN2 to of translation by in the sequence of little is the of translational control in of GCN2 J. Alcalde J. Mendez R. Pulido D. de Haro C. J. Biol. Chem. 1997; 272: 12544-12550Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 19Olsen D.S. Jordan B. Chen D. Wek R.C. Cavener D.R. Genetics. 1998; 149: 1495-1509Crossref PubMed Google indicates that regulatory mechanisms also in as of translation initiation by of eukaryotic Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: Scholar). of from Drosophila that a also in as amino acid and has been to eIF-2α phosphorylation in mammalian M.J. A. R. R. Hershey J.W.B. J. Biol. Chem. Full Text PDF PubMed Google Scholar). eIF-2α kinases have been in regulating protein synthesis in mammalian the to conditions are for by the PKR and kinases (6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar, J. 1988; PubMed Scopus Google Scholar, Biochem. J. 1989; PubMed Scopus Google Scholar, J. M.S. E. Hovanessian A. Virology. 1992; PubMed Scopus Google Scholar, R.C. Kimball S.R. Jefferson L.S. Biochem. 1993; Google Scholar, L. R. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). have and a eIF-2α kinase from pancreas, PEK, eIF-2α kinase K.M. R. J. J. Wek R.C. Mol. Cell. Biol. 1998; PubMed Google Scholar). In have and cDNA human We that the PEK eIF-2α kinase is from We show that the is specifically expressed in pancreatic and with somatostatin, a pancreatic islet delta cell-specific hormone. human PEK cDNA was by amplification cDNA from human and and The was by a and as a to cDNA with mRNA from human pancreas, and and was carried out to a by by two of the cDNA from by in from the as by cDNA was by a and was as a to a human to a by on and The cDNA was by amplification and from the of the PEK and as is an expressed sequence tag that of the of human PEK and of was carried out a to the and blot analysis of the carried out as by J. T. Laboratory Cold Spring Harbor Laboratory Press, Cold Spring Harbor, Scholar). with a of including and and the by in and with the to a by a and with an by and kinase and of the was carried out the conditions in cDNA was the of and the was was carried out a and and to a of the amino acid to alanine at of the PEK carried on The mutant PEK was to the amino acid and to that The mutant PEK was and from and the located on the expression The was cDNA the of human PEK and the and was by a from and a from the of The and the the including the the and the including the of the human PEK, The was The insert was released from the by with and and the in the expression The was of that and mutant PEK was carried out a expression with for the PEK or with for the mutant of the Sf-9 of and expression of PEK and mutant in Sf-9 carried out to the by the The of PEK from Sf-9 was in kinase eIF-2α as a of Sf-9 human PEK and Lys-614 mutant PEK or an protein in by at for to The with of by with of at for on a with of protein at for with the with and with kinase The eIF-2α kinase was carried out by of and of human eIF-2α and of to the and at for by with of for and by The and to at from the eIF-2α kinase by and to with for in the with for in the a in the for with in of PEK on the was carried out an from Northern of from human PEK cDNA from amplification was by a from and was in the Northern blot was carried out in and at by three at in with levels of PEK to was by a PEK and in The by of with from two of the PEK protein The was to a sequence in the kinase and the was to a sequence from the terminus of The also for and and human tissues in for and in and in in for to the complex The in with and for at with PEK or or with each of the to somatostatin, or in the three with the with and at for The three in and by human found to the PEK cDNA sequence when the sequence was as a to the from the human and cDNA from human a cDNA by analysis that the cDNA the part of the human PEK, and was as a to a cDNA with mRNA from human pancreas, and to human PEK of of the in the of a which carried a cDNA insert that the with PEK that the carried the of the and sequence that with the of the sequence was from two and which the cDNA to the cDNA insert of by at a to the of the PEK at the a at the of the PEK This is by to the sequence by rapid amplification of cDNA ends cDNA from different human tissues including pancreas, and sequence on the of the PEK was to the of the human PEK cDNA from the of the cDNA was as to a human to that the of PEK than and Northern blot that only one carried the of the cDNA was from the of that the the and the of the of human PEK that with the cDNA between the human sequence and the PEK cDNA to the cDNA sequence to which the of human analysis indicates that the the human PEK cDNA of of and of The the the for translation initiation M. J. Biol. Chem. 1991; 266: Full Text PDF PubMed Google Scholar). The a polypeptide with a of of the protein sequence indicates two One of the is located at the N and the other one is located in the of the The sequence a with to be a or a sequence for The PEK protein shares sequence and with The two differ within the N terminus regulatory where three of amino acid are present in the human The two of a are also conserved between the human and The kinase of human PEK to be related to PKR than the other two eIF-2α kinases, and yeast GCN2 In contrast, the of the PEK is the different physiological signals that regulate a of the protein the only sequence that homology to the regulatory is with an kinase from C. The C. polypeptide is in and shares and with human In contrast to within the kinase with HRI, and PEK shares with the C. in that the of the conserved are in The kinase differ from the mammalian in as the two of human and PEK are found in the C. The distinct homology between human PEK and other eIF-2α kinases that PEK is a eIF-2α To human PEK eIF-2α kinase activity, a cDNA human PEK and expressed the cDNA in Sf-9 cells. a to the terminus of PEK, human PEK from Sf-9 the a control for the kinase was also carried out from Sf-9 an of or of human eIF-2α and to the of human PEK in a phosphorylation of eIF-2α In contrast, phosphorylation of eIF-2α was detected in of the protein The human PEK protein to be as by the presence of a with the of human PEK, which is in the control with as by an at the in of PEK with autophosphorylation of the To the of the autophosphorylation of PEK is a for kinase activity, have a mutant PEK in which an alanine was for a at conserved the eIF-2α The mutant PEK, was expressed in Sf-9 and was in kinase In with the PEK, mutation of the conserved residue has completely abolished kinase activity, as eIF-2α phosphorylation was detected from from Sf-9 of or of human eIF-2α and to the kinase In contrast, the mutant PEK by the presence of a protein to the of PEK The mutation has also a in with by changes in of the The protein was by blot PEK to the of the protein The that the protein was the PEK Consistent with the high level of the level of mutant PEK protein was expressed at a level than that of the PEK, which was the of the with The results that the PEK kinase can be from The expression of PEK mRNA in various human tissues was by Northern blot analysis of RNA a cDNA from the of human This detected a mRNA in the tissues detected in of the tissues. PEK mRNA was detected in and PEK expression was also at lower levels in other tissues including and to the levels of lower within each that PEK was expressed in with an expression level that was than than and than than of the other tissues. The of which include and the We have two to PEK to and can be at a and was the analysis was carried out to PEK protein expression in human and various tissues including pancreas, large and The detected levels of PEK protein in within human and pancreatic In contrast, the expression level in the and in other tissues was by the The is with the high level of mRNA levels detected from pancreatic by the Northern blot of including delta and pancreatic cells. To the that the PEK protein in pancreatic islets, was for of PEK with cell-specific somatostatin, and pancreatic of the detected cell-specific expression of the the expression of co-localized with that of human PEK of the detected the The results that PEK is predominantly expressed in pancreatic delta cells. that eIF-2α kinase is for by and PKR (6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar, J. 1988; PubMed Scopus Google Scholar, Biochem. J. 1989; PubMed Scopus Google Scholar, J. M.S. E. Hovanessian A. Virology. 1992; PubMed Scopus Google Scholar, R.C. Kimball S.R. Jefferson L.S. Biochem. 1993; Google Scholar, L. R. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). Thus is to that with of the PKR an with only of to viral infection J. A. R. Kumar A. Williams B.R.G. M. C. J. 1995; PubMed Scopus Google Scholar). In to PKR and HRI, PEK is of amino with a large N terminus of the kinase PEK a insert between III and a which eIF-2α kinases from other families of serine/threonine kinases (20Hanks S.K. Hunter T. FASEB J. 1995; 9: 576-596Crossref PubMed Scopus (2280) Google Scholar). The of the insert between different eIF-2α kinases, and has been to be important in regulating eIF-2α kinase and J.J. London I.M. Trends Biochem. Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, R. Williams B.R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). eIF-2α phosphorylation is conserved from yeast to that a by mammalian to to infection by a of eIF-2α kinase, which a can of eIF-2α kinases in Sf-9 R. J. Kimball S.R. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). In to yeast also have been to the translational control of mammalian eIF-2α Gehrke L. Chen J.J. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google that the expression of inhibition of general protein synthesis in cells. inhibition was by of a mutant that carried an alanine on the phosphorylation It be that the level of expression of the PEK in Sf-9 is very low when with the level of mutant This is from the blot analysis of the PEK The low level of expression is by the of the We the of PEK in Sf-9 that infection of the the PEK when with with the mutant PEK of eIF-2α by PKR was to in yeast G.S. Chong K. Kumar A. Williams B.R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5447-5451Crossref PubMed Scopus (155) Google Scholar, Chen J.J. L. London I.M. Hinnebusch A.G. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar, S.R. Mathews M.B. Hinnebusch A.G. Mol. Cell. Biol. 1995; PubMed Google Scholar). The of PEK from of eIF-2α in the PEK have been to GCN2 in yeast K.M. R. J. J. Wek R.C. Mol. Cell. Biol. 1998; PubMed Google Scholar). The also from translational in Sf-9 by of PEK for binding with as by R. J. Kimball S.R. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). One of the features of PEK is the presence of a at the N which is conserved between and human is in the C. are with or of to different an important role in regulating kinase by to or regulatory double-stranded domains located at the N terminus of PKR have been to PKR with the ribosome S. Wek R.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (70) Google Scholar). is for of the kinase in though the double-stranded is phosphorylation of eIF-2α S. Wek R.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Consistent with the with the kinase has also been to be in the though the domains for have been S. T. M. M. Hovanessian A.G. M.J. Cell 1995; PubMed Scopus Google Scholar). GCN2 is also to ribosomal by a in the the sequence is conserved between GCN2 and is in that the to other amino acid the ribosomal and the kinase of PKR and yeast GCN2 in S. Wek R.C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In PEK regulatory as a double-stranded of PKR or binding of HRI. residue is and share homology with in the for an kinase from C. is that PEK is regulated by different It is that the and a in the of the play important in the kinase to C.E. J. Biol. Chem. 1993; 268: 7603-7606Abstract Full Text PDF PubMed Google Scholar, J.J. London I.M. Trends Biochem. Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, Trends Biochem. Sci. 1995; Full Text PDF PubMed Scopus Google Scholar, D.R. D.R. Hinnebusch A.G. M. Mathews M.B. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, D.R. C. Mathews M.B. J. Hinnebusch A.G. Mol. Cell. Biol. 1998; PubMed Google that autophosphorylation is for of the eIF-2α residue within the kinase of eIF-2α kinases has been to be important in regulating the kinase and and by PKR (6de Haro C. Mendez R. Santoyo J. FASEB J. 1996; 10: 1378-1388Crossref PubMed Scopus (236) Google Scholar). the of the residue in regulating has been of the residue with an or a was to completely PKR kinase The also abolished PKR autophosphorylation in in Galabru J. Hovanessian A.G. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google and in in a M. M. E. Chong K. Williams B.R. Hovanessian A.G. Mol. Cell. Biol. 1991; PubMed Scopus Google Scholar), that autophosphorylation is for eIF-2α kinase In contrast, the mutation was to only the kinase on autophosphorylation D.C. Samuel C.E. J. 1993; PubMed Google Scholar). We have a mutant PEK by the at with an alanine to PEK kinase is regulated by the level of Consistent with the PKR the to alanine mutation completely abolished kinase In contrast, the mutant PEK autophosphorylated when expressed in Sf-9 that the kinase is from a PEK also in Sf-9 is that the phosphorylation be carried out by an kinase in the level of expression of the mutant PEK is very high in Sf-9 only a of the mutant PEK be an is In contrast to that PEK kinase is by the of It be that though the PEK mRNA is detected in various analysis only detected the PEK protein in pancreatic The is of and that are within the only of in human is islet S. Scholar, M. M.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). the level of expression of can be by the of when in of are of at to form within the of the islet are are delta are or pancreatic and the other Thus the level of PEK mRNA in pancreatic islets, especially in pancreatic delta be than that in This protein levels in other tissues though mRNA was The expression of PEK detected by is also with K.M. R. J. J. Wek R.C. Mol. Cell. Biol. 1998; PubMed Google on PEK kinase in different tissues in which that PEK kinase was only detected in and pancreatic the various tissues The islet a role of in in and The islet by different in a regulated in response to changes in environmental conditions. the the concentration of is the important factor that the synthesis and of various islet The of several including and to the in a conditions. also an important role in levels by of and In contrast to regulation of the biosynthesis of within at the level of protein synthesis S. Kenna S. Ashcroft S.J. Biochem. J. 1992; 285: 563-568Crossref PubMed Scopus (71) Google Scholar, M. A. I. K. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of other and in the are also believed to be regulated at the translational level J.C. Biochem. J. 1991; PubMed Scopus Google Scholar, K. J.C. Biochem. J. PubMed Scopus Google Scholar, J.C. Biochem. J. 1989; PubMed Scopus Google Scholar), little is the mechanisms in the that PEK is an islet delta cell-specific eIF-2α kinase have important on of translational control in pancreatic islets, a that important in and as We for synthesis and in the for sequence We also and for the We are especially to and for to the