Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta.

Witte

Journal of Biological Chemistry

et al. 2000

114

Protein kinase C (PKC) is a novel Ca2؉ -independent PKC isoform, which is selectively expressed in skeletal muscle and hematopoietic cells, especially T cells. In T cells, it colocalizes with the T cell antigen receptor (TCR)⅐CD3 complex in antigen-stimulated T cells and is involved in the transcriptional activation of the interleukin-2 gene. In the present study, we report that PKC is tyrosine phosphorylated in Jurkat T cells upon TCR⅐CD3 activation. The Src family protein-tyrosine kinase, Lck, was critical in TCR-induced tyrosine phosphorylation of PKC. Lck phosphorylated and was associated with the regulatory domain of PKC both in vitro and in intact cells. This association was constitutive, but it was enhanced by T cell activation, with both Srchomology 2 and Src-homology 3 domains of Lck contributing to it. Tyrosine 90 (Tyr-90) in the regulatory domain of PKC was identified as the major phosphorylation site by Lck. A constitutively active mutant of PKC (A148E) could enhance proliferation of Jurkat T cells and synergized with ionomycin to induce nuclear factor of T cells activity. However, mutation of Tyr-90 into phenylalanine markedly reduced (or abolished) these activities. These results suggest that Lck plays an important role in tyrosine phosphorylation of PKC, which may in turn modulate the physiological functions of PKC during TCR-induced T cell activation. Protein kinase C (PKC)1 is a family of serine/threonine kinases that play critical roles in the regulation of differentiation and proliferation in many cell types and in the response to diverse stimuli (reviewed in Refs. 1 and 2). Products of the 10 known mammalian PKC genes are classified into four subfamilies of Ca 2ϩ -dependent (or conventional, PKC␣, -␤, and -␥), Ca 2ϩ -independent (or novel, PKC␦, -⑀, -, and -), atypical (PKC and /), and PKC/D enzymes. Activity of PKC enzymes is regulated by phosphorylation and binding of defined cofactors. Enzyme activation is associated with its redistribution among different cellular compartments, commonly from the cytosolic to the particulate (membrane) fraction. Studies indicate that PKC is also important during T cell activation. This is indicated by the ability of physiological T cell receptor (TCR) ligands to activate PKC and induce its translocation from the cytosol to the particulate fraction; by the ability of PKC inhibitors, or PKC depletion by prolonged phorbol ester treatment, to block lymphocyte signaling and activation; by the requirement for persistent PKC activation during mitogenic T cell activation; and, finally, by the diminished TCR⅐CD3-mediated proliferation in PKC-deficient T cells (reviewed in Ref. 3).PKC is a novel Ca 2ϩ

Section: Discussionmentioning

confidence: 99%

Section: Protein Kinase C (Pkc)mentioning

confidence: 99%

Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation

Witte

Journal of Biological Chemistry

et al. 2000

114

“…Much less is known about the regulation of the more recently discovered PKC 8, particularly at the mRNA level. PKC ~5 was shown to exert antiproliferative actions upon overexpression in CHO [7] or NIH 3T3 cells [8,9] and to cause differentiation in myeloid 32D cells [10]. PKC 8 is also a candidate for mediating the antiproliferative effects of phorbol esters observed in some pituitary and colon carcinoma cell lines [11,12].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of PKC δ‐ and downregulation of PKC α‐mRNA and protein by a phorbol ester in human T84 cells

1996

Protein kinase C (PKC) family members are downregulated by chronic activation at the protein level in most cell types. In T84 human epithelial cells 12-O-tetradecanoyl phorbol 13-acetate (TPA) caused persistent translocation of PKC 8 to the membrane compartment and a 400% increase of PKC 5-mRNA after 24 h. In contrast, PKC a protein was completely downregulated and its mRNA was decreased to 60% of control levels after 24 h. This is the first report of PKC 5-mRNA upregulation by TPA which was previously only shown for PKC[~. In view of the antimitogenic actions of PKC 5 this pattern of regulation may serve to preserve growth control even in the presence of chronic cell activation.

“…When overexpressed, it can slow the growth of fibroblasts (Mischak et al, 1993), and inhibit morphological transformation in a variety of systems (Li et al, 1996;Perletti et al, 1999). PKCd is phosphorylated on tyrosine residues in response to several different stimuli, usually as a result of SFK activity (Li et al, 1994;Denning et al, 1996;Blake et al, 1999;Kronfeld et al, 2000;Joseloff et al, 2002). SFKs processively phosphorylate several tyrosines on PKCd (with Tyr 311 being the first residue phosphorylated), and this causes the subsequent degradation of the protein.…”

Section: Other Sfk Mitogenic Targetsmentioning

confidence: 99%

The interplay between Src family kinases and receptor tyrosine kinases

2004

Src family tyrosine kinases (SFKs) are involved in a diverse array of physiological processes, as highlighted in this review. An overview of how SFKs interact with, and participate in signaling from, receptor tyrosine kinases (RTKs) is discussed. And also, how SFKs are activated by RTKs, and how SFKs, in turn, can activate RTKs, as well as how SFKs can promote signaling from growth factor receptors in a number of ways including participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements and motility, and survival are discussed.