Association of PKC δ and active Src in PMA-treated MCF-7 human breast cancer cells

Shanmugam, Malathy; Krett, Nancy L.; Peters, Carl A.; Maizels, Evelyn T.; Murad, Faris; Kawakatsu, Hisaaki; Rosen, Steven T.; Hunzicker-Dunn, Mary

doi:10.1038/sj.onc.1201684

Cited by 60 publications

(56 citation statements)

References 28 publications

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“…However, the reduced basal and induced levels of Src activity might explain why these cells have a severe defect in migration and cell cycle progression). 2 Because both the colocalization of PKC␦ and Src (9,29) and the colocalization of PTP␣ and PKC␦ (30) have been described, our data suggest a model according to which these molecules (most likely together with additional associated proteins like RACK) reside in a signaling complex, as has been described for the mitogen-activated protein kinases (reviewed in Ref. 26).…”

Section: Discussionmentioning

confidence: 76%

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Brandt

Goerke

Heuer

et al. 2003

Journal of Biological Chemistry

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Previously we have shown that protein kinase C (PKC)-mediated reorganization of the actin cytoskeleton in smooth muscle cells is transmitted by the nonreceptor tyrosine kinase, Src. Several authors have described how 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation of cells results in an increase of Src activity, but the mechanism of the PKC-mediated Src activation is unknown. Using PKC isozymes purified from Spodoptera frugiperda insect cells, we show here that PKC is not able to activate Src directly. Our data reveal that the PKC-dependent Src activation occurs via the activation of the protein tyrosine phosphatase (PTP) PTP␣. PTP␣ becomes activated in vivo after TPA stimulation. Further, we show that PKC␦ phosphorylates and activates only PTP␣ in vitro but not any other of the TPA-responsive PKC isozymes that are expressed in A7r5 rat aortic smooth muscle cells. To further substantiate our data, we show that cells lacking PKC␦ have a markedly reduced PTP␣ and Src activity after 12-O-tetradecanoylphorbol-13-acetate stimulation. These data support a model in which the main mechanism of 12-O-tetradecanoylphorbol-13-acetate-induced Src activation is the direct phosphorylation and activation of PTP␣ by PKC␦, which in turn dephosphorylates and activates Src.Protein kinase C (PKC) 1 is a family of phospholipid-dependent serine/threonine kinases comprising 10 isozymes differing in their molecular domain organization of up to 4 variable and 3 constant regions and in their functions. These PKC isozymes are subdivided into three classes: (i)the "conventional" cPKCs, PKC-␣, -␤ (␤I and ␤II), and -␥, which can be activated by phosphatidylserine (PS), diacyl glycerol (DAG), or phorbol esters through binding to the C1 domain and Ca 2ϩ through binding to a Ca 2ϩ -binding site in their second constant region, C2; (ii) the "novel" nPKCs, PKC-␦, -⑀, -, -, which lack the C2 region and thus are Ca-independent but still DAG-, PS-, and phorbol ester-responsive; and (iii) the "atypical" aPKCs, PKC-/ and -, which also lack the C2 region and, in addition, are devoid of a functional DAG-binding site. Hence, the atypical PKCs are only responsive to PS but not to DAG or phorbol ester (reviewed in Refs.

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Section: Discussionmentioning

confidence: 76%

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Brandt

Goerke

Heuer

et al. 2003

Journal of Biological Chemistry

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“…Lyn and Src, associate with PKC␦ (27)(28)(29). Whereas phosphorylated Tyr-52 in PKC␦ was shown to associate with the SH2 domain of Lyn and this interaction in intact mast cells was dependent on cross-linking of the high affinity receptor for IgE (27), the interaction between PKC␦ and Src did not require the SH2 domain of the latter (28) and occurred constitutively (27).…”

Section: Discussionmentioning

confidence: 99%

“…PKC Is Associated with Lck-Several recent studies reported that PKC␦ associates with Src family PTKs, and is phosphorylated on tyrosine, in transformed cells (28,29) and in activated mast cells (27). To investigate whether PKC associates with Lck, we first performed in vitro binding assays using GST-Lck fusion proteins.…”

Section: Pkc Is Phosphorylated By Lck In Vivo and In Vitro-mentioning

confidence: 99%

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

Liu

Witte

Liu

et al. 2000

Journal of Biological Chemistry

114

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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

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“…In cells transformed with Ras or v-Src, Src phosphorylates PKC␦ on tyrosine, inactivates PKC␦ catalytic function, and causes rapid degradation of PKC␦ (27). However, upon stimulation of various cells with phorbol ester, growth factors, or hormones, PKC␦ is phosphorylated on a tyrosine residue and catalytically activated (54,55). Tyrosine phosphorylation of PKC␦ also occurs in response to various apoptotic stimuli, including H 2 O 2 , UV radiation, etoposide, and ceramide (56,48,57,58).…”

Section: Discussionmentioning

confidence: 99%

Activation of Bak and Bax through c-Abl-Protein Kinase Cδ-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells

Choi

Kim

Kang

et al. 2006

Journal of Biological Chemistry

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Association of PKC δ and active Src in PMA-treated MCF-7 human breast cancer cells

Cited by 60 publications

References 28 publications

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

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

Activation of Bak and Bax through c-Abl-Protein Kinase Cδ-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells

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