Platelet-derived growth factor activates protein kinase C epsilon through redundant and independent signaling pathways involving phospholipase C gamma or phosphatidylinositol 3-kinase.

Moriya, Shigeharu; Kazlauskas, Andrius; Akimoto, Kazunori; Hirai, Syu Ichi; Mizuno, Keiko; Takenawa, Tadaomi; Fukui, Yoshihiro; Watanabe, Yutaka; Ozaki, Shoichiro; Ohno, Shigeo

doi:10.1073/pnas.93.1.151

Cited by 172 publications

(122 citation statements)

References 34 publications

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“…However, we have ruled out this possibility by determining that endogenous mRNA and protein level of p21 WAF1/Cip1 were unaffected by rottlerin pretreatment (Figure 2a). Consistent with our observation that PI 3-kinase played a role as an upstream effector of PKC in apicidin induction of p21 WAF1/Cip1 , PI 3-kinase has been demonstrated to be essential for PKCe activation by PDGF and other growth factors (Moriya et al, 1996). Furthermore, recent evidence suggests that PKCe signaling pathway could be mediated by PDK-1.…”

Section: Discussionsupporting

confidence: 77%

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

et al. 2003

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We previously reported that the activation of p21 WAF1/Cip1 transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKCe dominant-negative mutant, and antisense oligonucleotide to inhibit PKCe specifically, we found that among PKC isoforms, PKCe was required for the p21 WAF1/ Cip1 expression by apicidin. In addition to PKCe, PI 3-kinase appeared to participate in the activation of p21 WAF1/Cip1 promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominantnegative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21 WAF1/Cip1 promoter and p21 WAF1/Cip1 protein expression by apicidin. Furthermore, membrane translocation of PKCe in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKCe in the p21 WAF1/Cip1 promoter activation by apicidin. However, the p21 WAF1/Cip1 expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21 WAF1/Cip1 promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21 WAF1/Cip1 by apicidin. Taken together, these results suggest that the PI 3-kinase-PKCe signaling pathway plays a pivotal role in the expression of the p21 WAF1/Cip1 by apicidin.

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Section: Discussionsupporting

confidence: 77%

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

et al. 2003

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“…Our previous demonstration of the requirement of PKC and MAPK in PDGF-induced GJC blockade (16) supports such a mode of action. A partial response in the PI3K add-back mutant (F5ϩ740/751) is also in accord with this model since PDGF-induced activation of PKC can also be mediated by PI3K (11,60,61). Alternatively, PI3K may function via activating and stabilizing PLC␥ (62).…”

Section: Discussionsupporting

confidence: 51%

Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

Hossain

Jagdale

et al. 1999

Journal of Biological Chemistry

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The platelet-derived growth factor (PDGF) mediates its cellular functions via activation of its receptor tyrosine kinase followed by the recruitment and activation of several signaling molecules. These signaling molecules then initiate specific signaling cascades, finally resulting in distinct physiological effects. To delineate the PDGF signaling pathway responsible for the disruption of gap junctional communication (GJC), wild-type PDGF receptor ␤ (PDGFR␤) and a series of PDGFR␤ mutants were expressed in T51B rat liver epithelial cells. In cells expressing wild-type PDGFR␤, PDGF induced disruption of GJC and phosphorylation of a gap junctional protein, connexin-43 (Cx43), which required activation of mitogen-activated protein kinase, although involvement of additional factors was also evident. In the F5 mutant lacking binding sites for phosphatidylinositol 3-kinase, GTPase-activating protein, SHP-2, and phospholipase C␥1 (PLC␥1), PDGF induced mitogen-activated protein kinase, but failed to affect GJC or Cx43, indicating involvement of additional signals presumably initiated by one or more of the mutated binding sites. Examination of the single-site mutants revealed that PDGF effects were not mediated via a single signaling component. This was confirmed by the "add-back" mutants, which showed that restoration of either SHP-2 or PLC␥1 binding was sufficient to propagate the GJC inhibitory actions of PDGF. Further analysis showed that activation of PLC␥1 is involved in Cx43 phosphorylation, which surprisingly failed to correlate with GJC blockade. The results of our study demonstrate that PDGF-induced disruption of GJC can be mediated by multiple signaling pathways and requires participation of multiple components.

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“…Consistent with these in vitro studies, inhibition of PI 3-K blocks PDGF and insulin-dependent activation of p70 S6-K in vivo (44), insulin-dependent activation of PKC in vivo (45,46), and PDGFdependent membrane recruitment and activation of PKC⑀ in vivo (47). However, the enzymatic activity of PDK1 is not dependent on phosphoinositides (48).…”

supporting

confidence: 66%

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

Rameh

Cantley

1999

Journal of Biological Chemistry

918

681

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Phosphoinositide 3-kinases 1 are a subfamily of lipid kinases that catalyze the addition of a phosphate molecule specifically to the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinositides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes (Fig. 1). Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4-and 5-positions (PtdIns-4,5-P 2 ). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. To date, nine members of the PI 3-K family have been isolated from mammalian cells. They are grouped, as suggested by Domin and Waterfield (1), into three classes according to the molecules that they preferentially utilize as substrates. Four different lipid products can be generated by the different PI 3-K members: the singly phosphorylated form PtdIns-3-P; the doubly phosphorylated forms PtdIns-3,4-P 2 and PtdIns-3,5-P 2 ; and finally the triply phosphorylated form PtdIns-3,4,5-P 3 (Fig. 1).PI 3-K was first described as a PI kinase activity associated with the viral oncoproteins, v-Src, v-Ros, and polyomavirus middle T. Mutational studies of these oncoproteins more than 10 years ago indicated a critical role for the associated PI kinase in cell transformation (reviewed by Ref. 2).Recent advances in the field have been achieved by the development of new techniques to probe for the direct targets of PI 3-K lipid products. The chemical synthesis of short chain fatty acid versions of these lipids (3-5) has been a crucial step in determining the specificity of lipid-binding proteins. Additionally, new cloning strategies have been developed to isolate new lipid-binding proteins (6). Here we will review the most recent advances in our understanding of the role of PI 3-K in cell function by dissecting the contribution of each of its lipid products. PtdIns-3-PRegulation-PtdIns-3-P is constitutively present in both mammalian and yeast cells (7,8). It can be produced in vitro via phosphorylation of PtdIns by Class I, II, or III PI 3-Ks (Fig. 1). However, the majority of PtdIns-3-P in mammalian cells is probably produced by Class III PI 3-K (9). The mammalian Class III enzyme is highly related to the yeast Vps34 gene product (10) and, like the yeast enzyme, is specific for PtdIns and will not phosphorylate PtdIns-4-P or PtdIns-4,5-P 2 (11).Targets-PtdIns-3-P was recently shown to specifically interact with a 70-residue protein module called the FYVE finger domain. This domain is a special type of RING zinc finger that is characterized by two zinc-binding sites and a highly conserved stretch of basic residues surrounding the third zinc-coordinating cysteine. Liposomes containing PtdIns-3-P were shown to associate with several FYVE domains (15)(16)(17). Other phosphoinositides bound poorly ...

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Platelet-derived growth factor activates protein kinase C epsilon through redundant and independent signaling pathways involving phospholipase C gamma or phosphatidylinositol 3-kinase.

Cited by 172 publications

References 34 publications

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

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