Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase (JNK) potentiates the transactivation function of c-Jun. Protein kinase D (PKD), a downstream effector of protein kinase C (PKC), has been implicated in the attenuation of epidermal growth factor (EGF)-induced activation of JNK. In order to determine whether activated PKD is sufficient to modulate the EGF-JNK-c-Jun pathway, we have developed a cellular model system, utilizing human embryonic kidney cells (HEK 293), in which stably transfected, constitutively active or kinase dead mutants of PKD can be inducibly expressed by the insect hormone, ecdysone. Induced expression of constitutively active, but not kinase dead PKD, suppressed EGF stimulated c-Jun phosphorylation at Ser 63, demonstrating that activated PKD is sufficient to suppress c-Jun phosphorylation. This is the first demonstration that PKD modulates phosphorylation of the proto-oncogene c-Jun at a site critical for its ability to mediate cell proliferation and differentiation.
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PMID:Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation. 1140 72

Protein kinase D (PKD), a downstream effector of protein kinase C (PKC), is implicated in suppression of the c-Jun N-terminal kinase (JNK) signaling pathway, however, its mechanism of action is unclear. Transphosphorylation of the PKD activation loop at serines 744/748 by a PKC mediated signal transduction pathway enhances its catalytic activity. Here we show that PKD activation loop phosphorylation at serines 744/748 via PKC, or mutation of these serines to glutamic acid (PKD-S744/748E) also results in complex formation with JNK, indicating that suppression of JNK signaling by PKD involves a direct interaction with JNK. Because catalytically active PKD associates with JNK we determined whether it could phosphorylate the c-Jun N-terminus as a potential mechanism by which it suppresses c-Jun Ser 63 phosphorylation when it complexes with JNK. Purified human PKD and either wild-type PKD from phorbol 12, 13-dibutyrate (PDB)-stimulated cells or unstimulated constitutively active PKD (PKD-S744/748E), phosphorylated the c-Jun N-terminus between amino acids 1-89 at sites distinct from those phosphorylated by JNK. These results demonstrate, for the first time, phosphorylation dependent association of PKD with another signaling molecule and reveal a potential mechanism by which PKD could modulate the ability of JNK to phosphorylate c-Jun by phosphorylating alternative sites in the c-Jun N-terminus when it is complexed with JNK.
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PMID:Protein kinase D complexes with C-Jun N-terminal kinase via activation loop phosphorylation and phosphorylates the C-Jun N-terminus. 1194 98

Protein kinase D (PKD) has been established as a negative modulator of the c-Jun N-terminal kinase (JNK) signaling pathway. We previously demonstrated that induced expression of constitutively active PKD (PKD-S744/748E) that mimics phosphorylation by PKC is sufficient to attenuate epidermal growth factor (EGF) stimulated c-Jun Ser 63 phosphorylation, a natural substrate of JNK, in HEK 293 cells. Because the JNK pathway has been implicated in sustaining both lung and pancreatic cancerous phenotypes, we have utilized stable inducible expression of PKD-S744/748E in clones of A549 non-small cell lung cancer (NSCLC) and Panc1, pancreatic cancer cells to determine its effects on JNK signaling in the context of the cancerous phenotype. In contrast to HEK 293 cells, induced expression of PKD-S744/748E in either A549 NSCLC or Panc1 cells failed to attenuate EGF dependent phosphorylation of c-Jun, indicating that EGF stimulated JNK phosphorylation of c-Jun is uncoupled from PKD suppression in these cancer cells.
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PMID:Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells. 1264 40

Protein kinase D (PKD) is a serine-threonine kinase involved in the activation of a variety of cells. In mast cells, activation of PKD by cross-linking of high affinity receptor for IgE (FcepsilonRI) has been reported, but little is known for its effects on cytokine production. We investigated the roles of PKD on FcepsilonRI-induced activator protein-1 (AP-1) activation and proinflammatory cytokine productions in mast cells. Pharmacological inhibition of PKD strongly inhibited production of interleukin (IL)-13 and tumor necrosis factor (TNF)-alpha induced by FcepsilonRI stimulation, and the overexpression of PKD significantly increased the IL-13 and TNF-alpha production. Reporter assay revealed that the overexpression of PKD enhanced FcepsilonRI-induced IL-13 promoter activation, and that the 5'-flanking region of IL-13 gene from positions -110 to -52 was under the regulation of PKD. The overexpression of PKD enhanced the induction of AP-1 luciferase activity by FcepsilonRI stimulation, while it had no effect on luciferase activities dependent upon NF-kappaB and NF-AT activated by FcepsilonRI stimulation. In EMSA, c-Jun and c-Fos appear to be the major components of AP-1 complexes activated by FcepsilonRI stimulation. Moreover the overexpression of PKD strongly enhanced the phosphorylation of both c-Jun and c-Fos following FcepsilonRI stimulation. Although stress-activated protein kinase/c-Jun N-terminal kinase (JNK) is known to be an important regulator for c-Jun phosphorylation and AP-1 activation, overexpression and inhibition of PKD had no effects on JNK phosphorylation. These results suggest that PKD may play a pivotal role in FcepsilonRI-induced cytokine production in mast cells through the activation of c-Jun, c-Fos, and AP-1.
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PMID:High affinity receptor for IgE stimulation activates protein kinase D augmenting activator protein-1 activity for cytokine producing in mast cells. 1993 69