Signaling by the Germinal Center Kinase Family of Protein Kinases (1999)

mitogen-activated protein kinase amino acid(s) cluster of differentiation cell division cycle Cdc42/Rac interaction and binding GCK C-terminal extension of CTD C-terminal regulatory domain extracellular signal-regulated kinase germinal center kinase GCK-related GCK-like kinase hematopoietic progenitor kinase-1 kinase responsive to stress lymphocyte-oriented kinase MAPK kinase kinase MAPK/ERK kinase MAPK kinase MEK kinase mixed lineage kinase mammalian sterile twenty-like Nck-interacting kinase (not to be confused with NF-κB-inducing kinase, also called NIK) nuclear factor-κB p21-activated kinase Pro/Glu/Ser/Thr-rich really interesting new gene stress-activated protein kinase Src homology Ste20-like oxidant stress response kinase sporulation-specific tumor necrosis factor TNF receptor TNFR-associated factor Mammalian mitogen-activated protein kinase (MAPK)1 pathways regulate an extensive range of cellular processes including gene transcription, cytoskeletal organization, metabolite homeostasis, cell growth, and apoptosis. At the physiologic level, MAPK pathways are likely to be critical to the pathogenesis of a number of important clinical conditions including oncogenesis, diabetes, ischemic injury, arthritis, and septic shock. MAPK pathways have been widely conserved in eukaryotic cell evolution. At the heart of these pathways are so-called “core signaling modules” consisting of the MAPKs, which are activated by concomitant Tyr and Thr phosphorylation catalyzed by members of the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) family. MEKs, in turn, are activated by Ser/Thr phosphorylation catalyzed by protein kinases of several families collectively termed MAPK kinase kinases (MAP3Ks) (reviewed in Refs. 1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar, 2Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4223) Google Scholar, 3Herskowitz I. Cell. 1995; 80: 187-197Abstract Full Text PDF PubMed Scopus (863) Google Scholar).Mammalian cells possess at least six MAPK families, three of which have been characterized in some detail: the ERKs, the stress-activated protein kinases (SAPKs, also referred to as Jun N-terminal kinases or JNKs) and the p38s (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar, 2Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4223) Google Scholar). The ERK pathway is a major downstream target of the Ras proto-oncoprotein and has been reviewed extensively elsewhere (2Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4223) Google Scholar, 4Avruch J. Zhang X.-f. Kyriakis J.M. Trends Biochem. Sci. 1994; 19: 279-283Abstract Full Text PDF PubMed Scopus (540) Google Scholar). The SAPKs and p38s are, in most instances, poorly activated by mitogens and are instead potently and preferentially activated by a variety of environmental stresses (ionizing radiation, heat shock, oxidative stress, osmotic shock), inflammatory mediators of the TNF family (TNF, interleukin-1, CD40L, etc.), and the vascular responses to ischemia, reperfusion, and hypertension and associated humoral factors (angiotensin II, endothelin) (1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar). The SAPKs and p38s activate several transcription factors, most notably activator protein-1 (reviewed in Refs. 1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar and 5Karin M. Liu Z.-g. Zandi E. Curr. Opin. Cell Biol. 1997; 9: 240-246Crossref PubMed Scopus (2282) Google Scholar).The SAPKs are activated by at least two MEKs, SAPK/ERK-kinase-1 (also called MAPK kinase (MKK)-4) and MKK7. The p38s are also activated by at least two MEKs, MKK3 and MKK6 (6Sánchez I. Hughes R.T. Mayer B.J. Yee K. Woodgett J.R. Avruch J. Kyriakis J.M. Zon L.I. Nature. 1994; 372: 794-798Crossref PubMed Scopus (913) Google Scholar, 7Dérijard B. Raingeaud J. Barrett T. Wu L.-H. Han J. Ulevitch R.J. Davis R.J. Science. 1995; 267: 682-685Crossref PubMed Scopus (1405) Google Scholar, 8Tournier C. Whitmarsh A.J. Cavanagh J. Barrett T. Davis R.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7337-7342Crossref PubMed Scopus (339) Google Scholar, 9Holland P.M. Suzanne M. Campbell J.S. Noselli S. Cooper J.A. J. Biol. Chem. 1997; 272: 24994-24998Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 10Raingeaud J. Whitmarsh A.J. Barett T. Dérijard B. Davis R.J. Mol. Cell. Biol. 1996; 16: 1247-1255Crossref PubMed Scopus (1139) Google Scholar). The MAP3Ks upstream of the SAPKs and p38s are structurally divergent and differ widely in the spectrum of MEKs that they can activate in vivo and in vitro. Of these, only MEK kinase 1 (MEKK1) and mixed lineage kinases (MLK) 2 and 3 are demonstrably SAPK pathway-specific (11Yan M. Dai T. Deak J.C. Kyriakis J.M. Zon L.I. Woodgett J.R. Templeton D.J. Nature. 1994; 372: 798-800Crossref PubMed Scopus (658) Google Scholar, 12Xu S. Robbins D.J. Christerson L.B. English J.M. Vanderbilt C. Cobb M.H. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5291-5295Crossref PubMed Scopus (122) Google Scholar, 13Rana A. Gallo K. Godowski P. Hirai S.-i. Ohno S. Zon L.I. Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 19025-19028Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 14Hirai S.-i. Katoh M. Terada M. Kyriakis J.M. Zon L.I. Rana A. Avruch J. Ohno S. J. Biol. 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Chem. 1996; 271: 13675-13679Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar) (reviewed in Ref. 1Kyriakis J.M. Avruch J. J. Biol. Chem. 1996; 271: 24313-24316Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar).Although considerable progress has been made in the identification of the molecular components and regulatory relationships of which MAPK core signaling modules are composed, much less is known of how core signaling modules are linked to events at the cell surface. A bewildering array of potential upstream activating proteins has been implicated in the regulation of MAP3Ks, ranging from Ras superfamily GTPases to additional protein kinases and adapter proteins coupled to cytokine receptors. In particular the SAPKs and p38s can be activatedin vivo by Rac1, Cdc42Hs, and V12 Chp, members of the Rho subgroup of Ras family GTPases (21Coso O.A. Chiarello M. Yu J.-C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1559) Google Scholar, 22Minden A. Lin A. Claret F.-X. Abo A. Karin M. Cell. 1995; 81: 1147-1157Abstract Full Text PDF PubMed Scopus (1444) Google Scholar, 23Bagrodia S. Dérijard B. Davis R.J. Cerione R.A. J. Biol. Chem. 1995; 270: 27995-27998Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar, 24Aronheim A. Broder Y.C. Cohen A. Fritsch A. Belisle B. Abo A. Curr. Biol. 1998; 8: 1125-1128Abstract Full Text Full Text PDF PubMed Google Scholar). Most, but not all, Rac and Cdc42 effectors possess a Cdc42/Rac interaction and binding (CRIB) domain (25Burbelo P.D. Drechsel D. Hall A. J. Biol. Chem. 1995; 270: 29071-29074Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 26Tapon N. Nagata K. Lamarche N. Hall A. EMBO J. 1998; 17: 1395-1404Crossref PubMed Scopus (179) Google Scholar). Of note, p21-activated kinases (PAKs) possess CRIB motifs and are activated upon binding GTP-Rac1 or -Cdc42Hs (27Sells M.A. Chernoff J. Trends Cell Biol. 1997; 7: 162-167Abstract Full Text PDF PubMed Scopus (264) Google Scholar). Several MAP3Ks upstream of the SAPKs and p38s, including MEKK-1 and -4 and MLK-2 and -3, can also bind GTP-Rac1 and/or -Cdc42Hs.Recently, protein Ser/Thr kinases related to human germinal center kinase (GCK) have emerged as important potential players in the regulation of stress-activated MAPK core signaling pathways. This review will discuss what is known about the GCKs and their roles in MAPK pathway regulation.The kGCK Family: Structural Features of Group I and II EnzymesEleven mammalian protein kinases related to GCK have been cloned. In addition, there are Drosophila, Caenorhabditis elegans, and Dictyostelium homologues as well as twoSaccharomyces cerevisiae genes with defined phenotypes. All GCK homologues possess N-terminal kinase domains that are distantly related to those of the PAKs and extensive C-terminal regulatory domains (CTDs) (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 36Pombo C.M. Bonventre J.V. Molnár A. Kyriakis J. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 37Creasy C.L. Ambrose D.M. Chernoff J. J. Biol. Chem. 1996; 271: 21049-21053Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 38Taylor L.K. Wang H.-C. Erikson R.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10099-10104Crossref PubMed Scopus (141) Google Scholar, 39Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 40Kuramochi S. Moriguchi T. Kuida K. Endo J. Semba K. Nishida E. Karasuyama H. J. Biol. Chem. 1997; 272: 22679-22684Crossref PubMed Scopus (59) Google Scholar, 41Su Y.-C. Treisman J.E. Skolnik E.Y. Genes Dev. 1998; 12: 2371-2380Crossref PubMed Scopus (123) Google Scholar, 42Eichinger L. Bähler M. Dietz M. Eckerskorn C. Schleicher M. J. Biol. Chem. 1998; 273: 12952-12959Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 43Freisen H. Lunz R. Doyle S. Segall J. Genes Dev. 1994; 8: 2162-2175Crossref PubMed Scopus (107) Google Scholar, 44Phillipsen P. Schweitzer B. Yeast. 1991; 7: 265-273Crossref PubMed Scopus (82) Google Scholar) (Fig. 1). The distant homology between PAK and GCK kinase domains has led to the grouping of these kinases into a single family. However, GCKs do not possess CRIB motifs and do not bind Rho GTPases; moreover, the PAKs have C-terminal kinase domains (27Sells M.A. Chernoff J. Trends Cell Biol. 1997; 7: 162-167Abstract Full Text PDF PubMed Scopus (264) Google Scholar). Based on these strong differences, GCKs should be considered a distinct protein kinase family.GCKs can be subdivided into two broad groups based on their structural and functional properties. Group I GCKs are closely related to GCK itself and include GCK, GCK-related (GCKR), GCK-like kinase (GLK), hematopoietic progenitor kinase-1 (HPK1), Nck-interacting kinase (NIK, not to be confused with NF-κB-inducing kinase, also called NIK), andDrosophila Misshapen. These enzymes have been shown to activate selectively the SAPKs (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 41Su Y.-C. Treisman J.E. Skolnik E.Y. Genes Dev. 1998; 12: 2371-2380Crossref PubMed Scopus (123) Google Scholar). The C. elegansGCK MIG-15, an ortholog of NIK, is also a group I GCK (Fig. 1).The C-terminal domains of all group I GCKs include at least two proline/glutamic acid/serine/threonine (PEST) motifs and at least two polyproline consensus binding sites for proteins containing Src homology (SH)-3 domains (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 41Su Y.-C. Treisman J.E. Skolnik E.Y. Genes Dev. 1998; 12: 2371-2380Crossref PubMed Scopus (123) Google Scholar). Most significantly, however, all of the group I kinases possess a highly conserved ∼350-aa C-terminal region divided into two domains: a hydrophobic, leucine-rich domain and a 140–150-aa stretch, the C-terminal (CT) region (Fig. 1) (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar,41Su Y.-C. Treisman J.E. Skolnik E.Y. Genes Dev. 1998; 12: 2371-2380Crossref PubMed Scopus (123) Google Scholar). The leucine residues in the Leu-rich domains are not organized into leucine zippers nor are these domains sufficiently hydrophobic for membrane insertion (Fig. 1) (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). GCK, GCKR, and GLK are all activated in vivo by TNF, and their CTDs along with that of HPK1 are quite homologous. Similarity to the CT motif of NIK, although apparent, is less dramatic (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 44Phillipsen P. Schweitzer B. Yeast. 1991; 7: 265-273Crossref PubMed Scopus (82) Google Scholar). Studies of GCK and GCKR indicate that this domain is required for binding proteins of the TNF receptor-associated factor (TRAF) family and, possibly, for gating the binding of MAP3Ks (45Pombo C.M. Kehrl J.H. Sánchez I. Katz P. Avruch J. Zon L.I. Woodgett J.R. Force T. Kyriakis J.M. Nature. 1995; 377: 750-754Crossref PubMed Scopus (204) Google Scholar). 2J. Kehrl, personal communication. Group II GCKs (Ste20-like oxidant stress-activated kinase-1 (SOK1), kinase responsive to stress (Krs)-1, mammalian sterile twenty-like-1 (MST1)/Krs2, mammalian sterile twenty-like-3 (MST3), lymphocyte-oriented kinase (LOK), severin kinase, Sps1p, and Cdc15p) are structurally more similar to S. cerevisiae Sps1p than to group I kinases (36Pombo C.M. Bonventre J.V. Molnár A. Kyriakis J. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 37Creasy C.L. Ambrose D.M. Chernoff J. J. Biol. Chem. 1996; 271: 21049-21053Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 38Taylor L.K. Wang H.-C. Erikson R.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10099-10104Crossref PubMed Scopus (141) Google Scholar, 39Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 40Kuramochi S. Moriguchi T. Kuida K. Endo J. Semba K. Nishida E. Karasuyama H. J. Biol. Chem. 1997; 272: 22679-22684Crossref PubMed Scopus (59) Google Scholar, 42Eichinger L. Bähler M. Dietz M. Eckerskorn C. Schleicher M. J. Biol. Chem. 1998; 273: 12952-12959Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 43Freisen H. Lunz R. Doyle S. Segall J. Genes Dev. 1994; 8: 2162-2175Crossref PubMed Scopus (107) Google Scholar, 44Phillipsen P. Schweitzer B. Yeast. 1991; 7: 265-273Crossref PubMed Scopus (82) Google Scholar). These enzymes are less well understood, and the mammalian kinases do not activate any of the known MAPK pathways. Although group II GCKs share substantial catalytic domain homology with group I GCKs, their CTDs differ significantly from those of the group I enzymes.Functional Properties of Group I GCKs: SAPK Activation via Binding and Regulation of MAP3KsAlthough GCK is expressed in all tissues examined, in B lymphocytic follicular tissue it is restricted largely to the germinal center and not the surrounding mantle zone (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar). Germinal centers are regions of B follicular tissue wherein B lymphocyte differentiation and selection, including Ig class switching, occurs. These processes are driven by ligands of the TNF family including CD40L, CD30L, and TNF itself (47Cerutti A. Schaffer A. Shah S. Zan H. Liou H.-C. Goodwin R.G. Casali P. Immunity. 1998; 9: 247-256Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 48Matsumoto M. Mariathasan S. Nahm M.H. Baranyay F. Peschon J.J. Chaplin D.D. Science. 1996; 271: 1289-1291Crossref PubMed Scopus (341) Google Scholar). That cytokines of the TNF family can potently activate the SAPKs suggested that GCK might relay signals from these ligands to the SAPKs. Indeed, GCK is a potent and selective activator of the SAPK pathway (45Pombo C.M. Kehrl J.H. Sánchez I. Katz P. Avruch J. Zon L.I. Woodgett J.R. Force T. Kyriakis J.M. Nature. 1995; 377: 750-754Crossref PubMed Scopus (204) Google Scholar, 46Yuasa T. Ohno S. Kehrl J.H. Kyriakis J.M. J. Biol. Chem. 1998; 273: 22681-22692Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). Upon overexpression, GCK does not activate p38, the ERKs, or NF-κB. The other group I GCKs manifest a similar selectivity for the SAPKs (31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. EMBO J. 1997; 16: 1279-1290Crossref PubMed Scopus (214) Google Scholar, 34Diener K. Wang X.S. Chen C. Meyer C.F. Keesler G. Zukowski M. Tan T.-H. Yao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9687-9692Crossref PubMed Scopus (115) Google Scholar, 35Shi C.-S. Kehrl J.H. J. Biol. Chem. 1997; 272: 32102-32107Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 45Pombo C.M. Kehrl J.H. Sánchez I. Katz P. Avruch J. Zon L.I. Woodgett J.R. Force T. Kyriakis J.M. Nature. 1995; 377: 750-754Crossref PubMed Scopus (204) Google Scholar, 46Yuasa T. Ohno S. Kehrl J.H. Kyriakis J.M. J. Biol. Chem. 1998; 273: 22681-22692Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). Activation of the SAPKs by coexpressed GCK itself and by other group I GCKs occurs in the of and the kinases are (30Katz P. Whalen G. Kehrl J.H. J. Biol. Chem. 1994; 269: 16802-16809Abstract Full Text PDF PubMed Google Scholar, 31Kiefer F. Tibbles L.A. Anafi M. Janssen A. Zanke B.W. Lassam N. Pawson T. Woodgett J.R. Iscove N.R. EMBO J. 1996; 15: 7013-7025Crossref PubMed Scopus (195) Google Scholar, 32Hu M.C.-T. Qiu W.R. Wang X. Meyer C.F. Tan T.-H. Genes Dev. 1996; 10: 2251-2264Crossref PubMed Scopus (190) Google Scholar, 33Su Y.-C. Han J. Xu S. Cobb M. Skolnik E.Y. 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Chem. 1998; 273: 22681-22692Abstract Full Text Full Text PDF PubMed Scopus (241) Google and of the GCK CT the binding of GCK to of the Leu-rich domain binding is upon of the C-terminal domain of the GCK that of the GCK CTD a binding for T. Ohno S. Kehrl J.H. Kyriakis J.M. J. Biol. Chem. 1998; 273: 2