Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-ζ and Raf-1

Dijk, van Jitse; Hilkmann, Henk; Wj, van Blitterswijk

doi:10.1042/bj3250303

Cited by 68 publications

(62 citation statements)

References 32 publications

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“…Since PKC has been reported to be an upstream activator of MAPK (6,34,37) and MAPK has been postulated to phosphorylate several residues in the C-terminal pseudosubstrate domain of p70S6K, we considered the possibility that PKC regulates p70S6K through its carboxy-terminal domain. We therefore tested the ability of myr-PKC to cooperate with FIG.…”

Section: Resultsmentioning

confidence: 99%

p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex

Romanelli

Martin

Toker

et al. 1999

Molecular and Cellular Biology

179

169

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p70 S6 kinase (p70S6K) is an important regulator of cell proliferation. Its activation by growth factor requires phosphorylation by various inputs on multiple sites. Data accumulated thus far support a model whereby p70S6K activation requires sequential phosphorylations at proline-directed residues in the putative autoinhibitorypseudosubstrate domain, as well as threonine 389. Threonine 229, a site in the catalytic loop is phosphorylated by phosphoinositide-dependent kinase 1 (PDK-1). Experimental evidence suggests that p70S6K activation requires a phosphoinositide 3-kinase (PI3-K)-dependent signal(s). However, the intermediates between PI3-K and p70S6K remain unclear. Here, we have identified PI3-K-regulated atypical protein kinase C (PKC) isoform PKC as an upstream regulator of p70S6K. In coexpression experiments, we found that a kinase-inactive PKC mutant antagonized activation of p70S6K by epidermal growth factor, PDK-1, and activated Cdc42 and PI3-K. While overexpression of a constitutively active PKC mutant (myristoylated PKC [myr-PKC ]) only modestly activated p70S6K, this mutant cooperated with PDK-1 activation of p70S6K. PDK-1-induced activation of a Cterminal truncation mutant of p70S6K was also enhanced by myr-PKC . Moreover, we have found that p70S6K can associate with both PDK-1 and PKC in vivo in a growth factor-independent manner, while PDK-1 and PKC can also associate with each other, suggesting the existence of a multimeric PI3-K signalling complex. This work provides evidence for a link between a phorbol ester-insensitive PKC isoform and p70S6K. The existence of a PI3-K-dependent signalling complex may enable efficient activation of p70S6K in cells.

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Section: Resultsmentioning

confidence: 99%

p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex

Romanelli

Martin

Toker

et al. 1999

Molecular and Cellular Biology

179

169

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“…Therefore, PKC may activate ERK, at least partly, by direct phosphorylation of the MAPK kinase, MEK, in cells. However, the phosphorylation of the MAPK kinase kinase, Raf1, by PKC has also been reported (27) and may contribute to this Rasindependent ERK activation. As PKC has previously been shown to be a target of the PI3K-dependent kinase, PDK1 (23,25,45), we hypothesized that the membrane proximal region of Mpl activates ERK through IRS2/PI3K and PKC.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, PDK1, a kinase dependent on PI3K, can activate atypical isoforms of PKCs (23)(24)(25)(26). An atypical PKC isoform, PKC, has been implicated in Ras-independent ERK activation, either by direct phosphorylation of Raf1 (27) or of MEK (22), serving as a linker between PI3K and ERK pathway.…”

mentioning

confidence: 99%

The Roles of Phosphatidylinositol 3-Kinase and Protein Kinase Cζ for Thrombopoietin-induced Mitogen-activated Protein Kinase Activation in Primary Murine Megakaryocytes

Rojnuckarin¹,

Miyakawa²,

Fox³

et al. 2001

Journal of Biological Chemistry

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Thrombopoietin (TPO) stimulates a network of intracellular signaling pathways that displays extensive cross-talk. We have demonstrated previously that the ERK/mitogen-activated protein kinase pathway is important for TPO-induced endomitosis in primary megakaryocytes (MKs). One known pathway by which TPO induces ERK activation is through the association of Shc with the penultimate phosphotyrosine within the TPO receptor, Mpl. However, several investigators found that the membrane-proximal half of the cytoplasmic domain of Mpl is sufficient to activate ERK in vitro and support base-line megakaryopoiesis in vivo. Using BaF3 cells expressing a truncated Mpl (T69Mpl) as a tool to identify non-Shc/Ras-dependent signaling pathways, we describe here novel mechanisms of TPO-induced ERK activation mediated, in part, by phosphoinositide 3-kinase (PI3K). Similar to cells expressing full-length receptor, PI3K was activated by its incorporation into a complex with IRS2 or Gab2. Furthermore, the MEKphosphorylating activity of protein kinase C (PKC) was also enhanced after TPO stimulation of T69Mpl, contributing to ERK activity. PKC and PI3K also contribute to TPO-induced ERK activation in MKs, confirming their physiological relevance. Like in BaF3 cells, a TPO-induced signaling complex containing p85PI3K is detectable in MKs expressing T61Mpl and is probably responsible for PI3K activation. These data demonstrate a novel role of PI3K and PKC in steadystate megakaryopoiesis.Binding of TPO 1 to its receptor, the product of the protooncogene c-mpl, activates a wide variety of signaling molecules and pathways. As for other cytokine systems, it is becoming clear that the response to TPO is characterized by networks of multiple branching and converging signaling pathways, which display extensive cross-talk. As such, blockade of one signaling pathway can be compensated by alternate pathways. This may partially explain relatively mild hematopoietic phenotypes of mice in which supposedly critical signaling pathways are disrupted by homologous recombination (1-3). We demonstrated previously that the ERK/MAPK pathway is activated in response to TPO in both a BaF3 cell line engineered to express full-length Mpl (BaF3/Mpl) and in primary MKs, and plays an important role in MK endomitosis (4). Consistent with our results, MKs from mice engineered to express only a truncated Mpl receptor missing 60 residues from the COOH terminus of the cytoplasmic domain (T61 or ⌬60 mice) display a reduced capacity to activate ERK and have significantly decreased endomitotic capability after TPO administration in vivo (3). The classic pathway of ERK activation is via growth factor-induced Shc phosphorylation followed by its association with Grb2 (5), which then activates Sos, a nucleotide exchange factor for Ras (6). Consequently, ERK can be activated by Ras-GTP through Raf and MEK phosphorylation. Several groups have reported that Shc is strongly activated in response to TPO (7). Hence, Shc-dependent activation of Ras is likely to be an important mechanism...

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“…Alternatively, PI3K may function via activating and stabilizing PLC␥ (62). Although activation of PKC by these modulators can also lead to MAPK activation (16,59), additional mechanisms of PKC involvement are yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

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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Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-ζ and Raf-1

Cited by 68 publications

References 32 publications

p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex

p70 S6 Kinase Is Regulated by Protein Kinase Cζ and Participates in a Phosphoinositide 3-Kinase-Regulated Signalling Complex

The Roles of Phosphatidylinositol 3-Kinase and Protein Kinase Cζ for Thrombopoietin-induced Mitogen-activated Protein Kinase Activation in Primary Murine Megakaryocytes

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

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