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The JNK protein kinase is a member of the MAP kinase group that is activated in response to dual phosphorylation on threonine and tyrosine. Ten JNK isoforms have been identified in human brain by molecular cloning. These protein kinases correspond to alternatively spliced isoforms derived from the JNK1, JNK2 and JNK3 genes. The protein kinase activity of these JNK isoforms was measured using the transcription factors ATF2, Elk-1 and members of the Jun family (See Drosophila Jun-related antigen) as substrates. Treatment of cells with interleukin-1 (IL-1) causes activation of the JNK isoforms. This activation is blocked by expression of the MAP kinase phosphatase MKP-1. Comparison of the binding activity of the JNK isoforms demonstrates that the JNK proteins differ in their interaction with ATF2, Elk-1 and Jun (transcription factors. Individual members of the JNK group may therefore selectively target specific transcription factors in vivo (Gupta, 1996).
Jun kinases (JNKs) phosphorylate c-Jun more efficiently in comparison to JunD, but they do not phosphorylate JunB. No other MAP kinases are involved in c-Jun N-terminal phosphorylation in mammalian cells. Effective JNK substrates require a separate docking site and specification-conferring residues flanking the phosphoacceptor. The docking site increases the efficiency and specificity of the phosphorylation reaction. JunB contains a functional JNK docking site but lacks specificity-conferring residues. Insertion of such residues brings JunB under JNK control. JunD, by contrast, lacks a JNK docking site, but its phosphoacceptor peptide is identical to that of c-Jun. Efficient N-terminal c-Jun phosphorylation requires dimerization. Substrates such as JunD can be phosphorylated by JNK through heterodimerization with docking competent partners. Therefore, heterodimerization can affect the recognition of transcription factors by signal-related protein kinases (Kallunki, 1996).
Stimulation of c-Jun transcriptional activity via phosphorylation mediated by the stress-activated or c-Jun amino-terminal (SAPK/JNK) subgroup of mitogen-activated protein kinases (MAP kinases) is thought to depend on a kinase-docking site (the delta region) within the amino-terminal activation domain, which is deleted from the oncogenic derivative, v-Jun. This mutation markedly enhances v-Jun oncogenicity; however, its transcriptional consequences have not been resolved. In part, this reflects uncertainty as to whether binding of SAPK/JNK inhibits c-Jun function directly or, alternatively, serves to facilitate and maintain the specificity of positive regulatory phosphorylation. Using a two-hybrid approach, it is shown that SAPK/JNK stimulates c-Jun transactivation in yeast and that this depends on both catalytic activity and physical interaction between the kinase and its substrate. Furthermore, c-Jun is active when tethered to DNA via SAPK/JNK, demonstrating that kinase binding does not preclude transactivation. Taken together, these results suggest that SAPK/JNK acts primarily as a positive regulator of c-Jun transactivation in situ, and that loss of the docking site physically uncouples v-Jun from this control. This loss-of-function model accounts for the deficit of v-Jun regulatory phosphorylation and repression of TPA response element (TRE)-dependent transcription observed in v-Jun-transformed cells and predicts that an important property of the oncoprotein is to antagonize SAPK/JNK-dependent gene expression. This conclusion challenges the long-standing assumption that v-Jun represents a 'super-activated' form of c-Jun, and predicts that V-Jun acts as a 'dominant negative' mutant that will block or antagonize SAPK/JNK-regulated gene expression. It is therefore suggested that repression of growth-inhibitory or pro-apoptotic genes may be more closely linked to v-Jun-mediated oncogenesis than is activation of growth-stimulatory genes, as previously supposed (May, 1998).
The nuclear function of the c-Abl tyrosine kinase is not well understood. In order to identify nuclear substrates of Abl, a constitutively active and nuclear form of the protein was constructed. Active nuclear Abl efficiently phosphorylates c-Jun, a transcription factor not previously known to be tyrosine phosphorylated. After phosphorylation of c-Jun by Abl on Tyr170, c-Jun and Abl interact via the SH2 domain of Abl. Surprisingly, elevated levels of c-Jun activate nuclear Abl, resulting in activation of the JNK serine/threonine kinase. This phosphorylation circuit generates nuclear tyrosine phosphorylation and represents a reversal of previously known signaling models (Barila, 2000).
These data can be summarized in a model, according to which elevated c-Jun levels can activate Abl in the nucleus. Activation requires the central part of the c-Jun protein and the presence of Tyr170 in order to be efficient. In turn, and consistent with previous reports, activation of nuclear Abl results in an increase in JNK activity. This may occur through a mechanism that involves a positive effect on a JNK activator, a negative effect on a JNK repressor, or it could even be direct. Once activated, JNK may then phosphorylate c-Jun at the N-terminal sites and increase c-Jun stability, DNA binding and transcriptional activity. If JNK then dissociates from Jun after phosphorylation, as proposed, this would allow more JNK-free Jun to activate Abl and result in a positive feedback loop (Barila, 2000).
The mechanism by which c-Jun could achieve activation of nuclear Abl is not clear. One possibility is that c-Jun activates Abl allosterically, by direct binding to Abl. The data show that nuclear Abl is regulated by intramolecular interactions involving the SH2-catalytic domain linker, as occurs for the bulk cellular Abl protein and for Abl synthesized in reticulocyte lysate. It is assumed that c-Jun binding to Abl may interfere with the regulatory intramolecular interactions. Initially, tyrosine phosphorylation of c-Jun may not be required for this activation and could occur, for example, via interaction of the proline-rich sequences in c-Jun with the Abl SH3 domain. Alternatively, basal phosphorylation of c-Jun by Abl may suffice to initiate the positive feedback loop. Although Abl and/or Arg seem to be required for c-Jun activation of JNK, the possibility cannot be excluded that c-Jun, or other AP-1 family members, can activate JNK by a mechanism that does not involve Abl in other cell types or under different physiological circumstances. It will be interesting to test whether some of the severe defects in mice lacking c-Jun can be attributed to defects in activating JNK or related kinases (Barila, 2000 and references therein).
Electrical stimulation of contractions (pacing) of primary neonatal rat ventricular myocytes increases intracellular calcium and activates a hypertrophic growth program that includes expression of the cardiac-specific gene, atrial natriuretic factor (ANF). To investigate the mechanism whereby pacing increases ANF, pacing was tested for its ability to regulate mitogen-activated protein kinase family members, ANF promoter activity, and the trans-activation domain of the transcription factor, Sp1. Pacing and the calcium channel agonist BAYK 8644 activate c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated kinase. Pacing stimulates ANF-promoter activity approximately 10-fold. Transfection with an expression vector for c-Jun, a substrate for JNK, also activates the ANF promoter; the combination of pacing and c-Jun is synergistic, consistent with roles for JNK and c-Jun in calcium-activated ANF expression. Proximal serum response factor and Sp1 binding sites are required for the effects of pacing or c-Jun on the ANF promoter. Pacing and c-Jun activate a GAL4-Sp1 fusion protein by 3- and 12-fold, respectively, whereas the two stimuli together activate GAL4-Sp1 synergistically, similar to their effect on the ANF promoter. Transfection with an expression vector for c-Fos inhibits the effects of c-Jun, suggesting that c-Jun acts independently of AP-1. These results demonstrate an interaction between c-Jun and Sp1 and are consistent with a novel mechanism of calcium-mediated transcriptional activation involving the collaborative actions of JNK, c-Jun, serum response factor, and Sp1 (McDonough, 1997).
Adenovirus E1B proteins (19,000-molecular-weight [19K] and 55K proteins) inhibit apoptosis and cooperate with adenovirus E1A to induce full oncogenic transformation of primary cells. The E1B 19K protein has previously been shown to be capable of activating transcription; however, the underlying mechanisms are unclear. Adenovirus infection is shown to activate the c-Jun N-terminal kinase (JNK) and the E1B gene products are shown to be necessary for adenovirus to activate JNK. The E1B 19K protein is sufficient to activate JNK and can strongly induce c-Jun-dependent transcription. Mapping studies show that the C-terminal portion of E1B 19K is necessary for the induction of c-Jun-mediated transcription. Using dominant-negative mutants of several kinases upstream of JNK, it has been shown that MEKK1 and MKK4, but not Ras, are involved in the induction of JNK activity by adenovirus infection. The same dominant-negative kinase mutants also block the ability of E1B 19K to induce c-Jun-mediated transcription. Taken together, these results suggest that E1B 19K may utilize the MEKK1-MKK4-JNK signaling pathway to activate c-Jun-dependent transcription and demonstrate a novel, kinase-activating activity of E1B 19K that may underlie its ability to regulate transcription (See, 1998).
ATF3 gene, which encodes a member of the activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors, may be induced by any of a number of physiological stresses. The human ATF3 mRNA is derived from four exons distributed over 15 kilobases. Sequence analysis of the 5'-flanking region reveals a consensus TATA box and a number of transcription factor binding sites including the AP-1, ATF/CRE, NF-kappa B, E2F, and Myc/Max binding sites. The ATF3 gene is induced by stress signals. Anisomycin at a low concentration activates the ATF3 promoter and stabilizes the ATF3 mRNA. Significantly, co-transfection of DNAs expressing ATF2 and c-Jun activates the ATF3 promoter. G. Liang and others (1996) discuss a possible mechanism implicating the C-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) stress-inducible signaling pathway in the induction of the ATF3 gene (Liang, 1996).
Human heat shock transcription factor 1 (HSF1) is responsible for stress-induced transcription of heat shock protein genes. The activity of the HSF1 transcriptional activation domains is modulated by a separate regulatory domain, which confers repression at control temperature and heat inducibility. High level of phosphorylation at the low (control) temperature seems to result in HSF1 inactivation. Two specific proline-directed serine motifs are important for function of the regulatory domain: mutation of these serines to alanine results in derepressed HSF1 activity at control temperature, and mutation to glutamic acid, mimicking a phosphorylated serine, results in normal repression at control temperature, with normal heat shock inducibility. Tryptic mapping shows that these serines are the major phosphorylation sites of HSF1 at control temperature in vivo. Stimulation of the Raf/ERK pathway in vivo results in an increased level of phosphorylation of these major sites. The regulatory domain is an excellent substrate in vitro for the mitogen-activated MAPK/ERK. Phosphorylation of the regulatory domain of HSF1 appears to decrease the activity of HSF1 at control temperature, and suggests a mechanism for modification of HSF1 activity by growth control signals (Knauf, 1996).
The nuclear factor of activated T cells (NFAT) group of transcription factors is retained in the cytoplasm of quiescent cells. NFAT activation is mediated in part by induced nuclear import. This process requires calcium-dependent dephosphorylation of NFAT caused by the phosphatase calcineurin. The c-Jun amino-terminal kinase (JNK) phosphorylates NFAT4 on two sites. Mutational removal of the JNK phosphorylation sites causes constitutive nuclear localization of NFAT4. In contrast, JNK activation in calcineurin-stimulated cells causes nuclear exclusion of NFAT4. These findings show that the nuclear accumulation of NFAT4 promoted by calcineurin is opposed by the JNK signal transduction pathway. The negative regulation of NFAT4 nuclear accumulation caused by JNK provides a mechanism for cell type-specific responses to extracellular stimulation. Thus, JNK activation causes increased AP-1 transcriptional activity that cooperates with calcium-stimulated nuclear accumulation of NFAT3, NFATp and NFATc. In contrast JNK activation blocks NFAT nuclear accumulation in cells that express NFAT4. Therefore the NFAT4 isoform serves to integrate negative signals from JNK into the NFAT signaling pathway (Chow, 1997).
The activation of the mitogen-activated protein kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 results in phosphorylation and activation of transcription factors that promote proliferative and inflammatory responses, whereas glucocorticoid receptor (GR) activation inhibits cell growth and inflammation. JNK and ERK (but not p38) phosphorylate GR in vitro, primarily at Ser-246. Selective activation of either ERK or JNK in vivo inhibits GR-mediated transcriptional activation, which depends on receptor phosphorylation at Ser-246 by JNK but not ERK. Thus, JNK inhibits GR transcriptional activation by direct receptor phosphorylation, whereas ERK does so indirectly. It is proposed that phosphorylation of GR by JNK or of a GR cofactor by ERK provides mechanisms to ensure the rapid inhibition of GR-dependent gene expression when it conflicts with mitogenic or proinflammatory signals (Rogatsky, 1998).
The E2F transcription factor plays a major role in cell cycle regulation, differentiation and apoptosis, but it is not clear how it is regulated by non-mitogenic signaling cascades. Two kinases involved in signal transduction have opposite effects on E2F function: the stress-induced kinase JNK1 inhibits E2F1 activity whereas the related p38 kinase reverses Rb-mediated repression of E2F1. JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1; treatment of cells with TNFalpha has a similar effect. Fas stimulation of Jurkat cells is known to induce p38 kinase and a pronounced increase in Rb phosphorylation is found within 30 min of Fas stimulation. Phosphorylation of Rb correlates with a dissociation of E2F and increased transcriptional activity. The inactivation of Rb by Fas is blocked by SB203580, a p38-specific inhibitor, as well as a dominant-negative p38 construct; cyclin-dependent kinase (cdk) inhibitors as well as dominant-negative cdks have no effect. These results suggest that Fas-mediated inactivation of Rb is mediated via the p38 kinase, independent of cdks. The Rb/E2F-mediated cell cycle regulatory pathway appears to be a normal target for non-mitogenic signaling cascades and could be involved in mediating the cellular effects of such signals (Wang, 1999).
The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein kinases is stimulated in response to a wide array of cellular stresses and proinflammatory cytokines. Mice lacking individual members of the Jnk family (Jnk1, Jnk2, and Jnk3) are viable and survive without overt structural abnormalities. Mice with a compound deficiency in Jnk expression can survive to birth, but fail to close the optic fissure (retinal coloboma). JNK initiates a cytokine cascade of bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh) that induces the expression of the paired-like homeobox transcription factor Pax2 and closure of the optic fissure. BMP4 is under the control of JNK. In vitro studies using retinal explant cultures indicate that the function of BMP4, in part, is to induce the expression of Shh in a cytokine cascade that leads to the expression of the paired-like homeobox transcription factor Pax2. Interestingly, the role of JNK to regulate BMP4 expression during optic fissure closure is conserved in Drosophila during dorsal closure, a related morphogenetic process that requires JNK-regulated expression of the BMP4 ortholog Decapentaplegic (Weston, 2003).
BMP4 has been implicated in the regulation of Shh expression in the mouse. To test whether BMP4 regulates the expression of Shh and Pax2 in the eye, retinal explant cultures were examined. Consistent with in vivo results, strong expression of both Shh and Pax2 was detected in control retinas, but not in mutant retinas. When the mutant retinas were cultured in the presence of BMP4 for 48 h, induced expression of both Shh and Pax2 was detected, indicating that BMP4 is sufficient to cause expression of Shh and Pax2, and that the BMP4-Shh-Pax2 pathway is intact in the JNK-deficient mutant embryonic eyes. In contrast, no BMP4-stimulated expression of Shh or Pax2 in the mutant retinas was detected in the absence or presence of an antagonistic antibody to Shh. Similarly, when control retinas were cultured in the presence of BMP4 plus the antagonistic antibody to Shh, there was a dramatic decrease in both Shh and Pax2 expression. These data imply that BMP4 induces the expression of Shh and Pax2 in mutant retinas, and that Shh is upstream of Pax2 expression. This signaling cascade is initiated by JNK and is absent in JNK-deficient retinas (Weston, 2003).
It is striking that the effects of Pax2 deficiency are similar to those caused by JNK deficiency. For example, both of these mutations cause failure of optic fissure closure (coloboma) and renal epithelial cell necrosis. Furthermore, both mutations alter the expression of Shh at the basis of the diencephalon in E9.5 embryos. These similar phenotypes are most likely accounted for by the observation that Pax2 expression is markedly reduced in the eyes and kidney epithelium of JNK-deficient mice. A further contributing factor may be that JNK can phosphorylate Pax2. However, because the level of Pax2 mRNA and protein in JNK-deficient eyes is extremely low, the role of altered Pax2 phosphorylation is unclear (Weston, 2003).
The c-Jun amino-terminal kinase (JNK) is generally thought to be involved in inflammation, proliferation and apoptosis. Accordingly, its substrates are transcription factors and antiapoptotic proteins. However, JNK has also been shown to be required for Drosophila dorsal closure, and MAP kinase/ERK kinase kinase 1, an upstream kinase in the JNK pathway, has been shown to be essential for cell migration. Both results imply that JNK is important in cell migration. JNK1 is shown to be required for the rapid movement of both fish keratocytes and rat bladder tumor epithelial cells (NBT-II). Moreover, JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (PaxS178A) form focal adhesions and exhibit the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin move rapidly and retain close contacts as the predominant adhesion. Expression of PaxS178A also inhibits the migration of two other cell lines. Thus, phosphorylation of paxillin by JNK seems essential for maintaining the labile adhesions required for rapid cell migration (Huang, 2003).
Cell signaling affects gene expression by regulating the activity of transcription factors. Mitogen-activated protein kinase (MAPK) phosphorylation of Ets-1 and Ets-2 occurs at a conserved site N terminal to their Pointed (PNT) domains. This results in enhanced transactivation by preferential recruitment of the coactivators CREB binding protein (CBP) and p300. This phosphorylation-augmented interaction was discovered in an unbiased affinity chromatography screen of HeLa nuclear extracts by using either mock-treated or ERK2-phosphorylated ETS proteins as ligands. Binding between purified proteins has demonstrated a direct interaction. Both the phosphoacceptor site, which lies in an unstructured region, and the PNT domain are required for the interaction. Minimal regions that are competent for induced CBP/p300 binding in vitro also support MAPK-enhanced transcription in vivo. CBP coexpression potentiates MEK1-stimulated Ets-2 transactivation of promoters with Ras-responsive elements. Furthermore, CBP and Ets-2 interact in a phosphorylation-enhanced manner in vivo. This study describes a distinctive interface for a transcription factor-coactivator complex and demonstrates a functional role for inducible CBP/p300 binding. In addition, these findings decipher the mechanistic link between Ras/MAPK signaling and two specific transcription factors that are relevant to both normal development and tumorigenesis (Foulds, 2004).
Cells respond to a variety of extracellular and intracellular forms of stress by down-regulating rRNA synthesis. The mechanism underlying stress-dependent inhibition of RNA polymerase I (Pol I) transcription has been investigated: the Pol I-specific transcription factor TIF-IA is inactivated upon stress. Inactivation is due to phosphorylation of TIF-IA by c-Jun N-terminal kinase (JNK) at a single threonine residue (Thr 200). Phosphorylation at Thr 200 impairs the interaction of TIF-IA with Pol I and the TBP-containing factor TIF-IB/SL1, thereby abrogating initiation complex formation. Moreover, TIF-IA is translocated from the nucleolus into the nucleoplasm. Substitution of Thr 200 by valine as well as knock-out of Jnk2 prevent inactivation and translocation of TIF-IA, leading to stress-resistance of Pol I transcription. These data identify TIF-IA as a downstream target of the JNK pathway and suggest a critical role of JNK2 to protect rRNA synthesis against the harmful consequences of cellular stress (Mayer, 2005).
The GLHs (germline RNA helicases), homologs of Drosophila Vasa, are constitutive components of the germline-specific P granules in the nematode C. elegans and are essential for fertility, yet how GLH proteins are regulated remains unknown. KGB-1 and CSN-5 are both GLH binding partners, previously identified by two-hybrid interactions. KGB-1 is a MAP kinase in the Jun N-terminal kinase (JNK) subfamily, whereas CSN-5 is a subunit of the COP9 signalosome. Intriguingly, although loss of either KGB-1 or CSN-5 results in sterility, their phenotypes are strikingly different. Whereas csn-5 RNA interference (RNAi) results in under-proliferated germlines, similar to glh-1/glh-4(RNAi), the kgb-1(um3) loss-of-function mutant exhibits germline over-proliferation. When kgb-1(um3) mutants are compared with wild-type C. elegans, GLH-1 protein levels are as much as 6-fold elevated and the organization of GLH-1 in P granules is grossly disrupted. A series of additional in vivo and in vitro tests indicates that KGB-1 and CSN-5 regulate GLH-1 levels, with GLH-1 targeted for proteosomal degradation by KGB-1 and stabilized by CSN-5. It is proposed the 'good cop: bad cop' team of CSN-5 and KGB-1 imposes a balance on GLH-1 levels, resulting in germline homeostasis. In addition, both KGB-1 and CSN-5 bind Vasa, a Drosophila germ granule component; therefore, similar regulatory mechanisms might be conserved from worms to flies (Orsborn, 2007).
The regulation of the c-Jun NH2-terminal kinase (JNK) subfamily of mitogen-activated protein kinases (MAPKs), in response to the inhibition of DNA replication, was examined during the cell cycle of human T-lymphocytes. JNK is rapidly activated following release of T-lymphocytes from G1/S-phase arrest and this activation precedes resumption of DNA synthesis upon S-phase progression. Activation of JNK correlates with dissociation of the cyclin-dependent protein kinase (CDK) inhibitor, p21WAF1, from JNK1. Since JNK1 isolated from T-lymphocytes by immunoprecipitation can be inhibited by recombinant p21WAF1 in vitro, these data suggest that JNK activation may be regulated in part by its dissociation from p21WAF1. The observation of a dynamic, physical association of native JNK1 and p21WAF1 in vivo has not previously been described and suggests a novel mechanism for JNK-mediated regulation of the cell cycle of human T-lymphocytes (Patel, 1998).
RhoA (see Drosophila Rho1) and two other Rho-family proteins, Cdc42 and Rac1, regulate Serum Response Factor (SRF) activation of the c-fos serum response element. This pathway acts independently of known MAPK pathways and is regulated by agents such as serum and LPA, acting via heterotrimeric G protein-coupled receptors. Constitutively active forms of either of the small GTPases -- RhoA (RhoA.V14) or Cdc42 (Cdc42.V12) -- induces expression of extrachromosomal SRF reporter genes in microinjection experiments, but only Cdc42.V12 can efficiently activate a chromosomal template. Both SAPK/JNK-dependent or -independent signals can cooperate with RhoA.V14 to activate chromosomal SRF reporters; it is SAPK/JNK activation by Cdc42.V12 that allows SAPK/JNK to activate chromosomal templates. Cooperating signals can be bypassed by deacetylase inhibitors. Three findings show that histone H4 hyperacetylation is one target for cooperating signals, although it alone is not sufficient: (1) Cdc42.V12, but not RhoA.V14, induces H4 hyperacetylation; (2) cooperating signals use the same SAPK/JNK-dependent or -independent pathways to induce H4 hyperacetylation, and (3) growth factor and stress stimuli induce substantial H4 hyperacetylation, detectable in reporter gene chromatin. These data establish a link between signal-regulated acetylation events and gene transcription. Thus, in isolation, the SRF-controlled extrachromosomal reporter gene is a target for only a subset of signals that can activate the chromsomal c-fos promoter. This is thought to reflect differences in chromatin structure associated with the two types of templates (Alberts, 1998a).
In order to define JNK roles in development, mice lacking both c-Jun-NH2 -terminal kinases (JNK1 and JNK2) were generated. Jnk1/jnk2 double mutant fetuses die around embryonic day 11 (E11) and display an open neural tube (exencephaly) at the hindbrain level with reduced apoptosis in the hindbrain neuroepithelium at E9.25. In contrast, a dramatic increase in cell death is observed one day later at E10.5 in both the hindbrain and forebrain regions. Moreover, about 25% of jnk1-/-jnk2+/- fetuses display exencephaly, probably due to reduced levels of JNK proteins, whereas jnk1+/-jnk2-/- mice are viable. These results assign both pro- and anti-apoptotic functions to JNK1 and JNK2 in the development of the fetal brain (Sabapathy, 1999b).
The absence of JNK1 and JNK2 has no effect on expression of c-Jun or its basal N-terminal phosphorylation in the CNS. Thus, c-Jun is unlikely to be involved in neural tube closure or other aspects of CNS morphogenesis. These results suggest that in the CNS, JNK3 phosphorylates c-Jun, while JNK1 and JNK2 must have other targets. Moreover, c- jun deficient fetuses, which survive up to E12.5, do not show defects in cranial morphogenesis. Conditional c-Jun mouse mutants were generated in which c-jun was deleted in nestin-expressing neurons by Cre-recombinase activity. These mice do not show any cranial morphogenetic defects. Together, these data argue strongly against c-Jun being a critical target for JNK1 and JNK2 in the control of CNS morphogenesis. Mutants lacking other JNK substrates were also generated, including ATF-2 and ATF-alpha. These mutants are viable and do not show developmental cranial defects. It is therefore possible that JNK1 and JNK2 are required in combination to phosphorylate multiple targets, which are then required for proper neural tube morphogenesis. This would add another level of control over the substrates, thus increasing the complexity of the signaling cascade (Sabapathy, 1999b).
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