Phospholipase D Stimulation by Receptor Tyrosine Kinases Mediated by Protein Kinase C and a Ras/Ral Signaling Cascade

Voß, Matthias; Weernink, Paschal A. Oude; Haupenthal, S.; Möller, Ulrike; Cool, Robbert H.; Bauer, Brigitte; Camonis, Jacques; Jakobs, Karl H.; Schmidt, Martina

doi:10.1074/jbc.274.49.34691

Cited by 61 publications

(17 citation statements)

References 47 publications

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“…The activation of PLD by EGF is dependent upon RalA (23,45), as was the EGF receptor endocytosis reported here. Consistent with these data, RalA was recently reported to be required for EGF-induced receptor endocytosis (29).…”

Section: Discussionmentioning

confidence: 75%

“…It was recently reported that EGF-induced PLD activity is dependent upon RalA (23,45), a Ras family GTPase (9) that is associated with PLD1 (14,25). The generation of EGFR cells that also overexpress either wild-type RalA or a dominant negative allele of RalA (S28N) was described previously (23).…”

Section: Fig 2 Egf-induced Receptor Degradation Is Inhibited By Primentioning

confidence: 99%

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Role for Phospholipase D in Receptor-Mediated Endocytosis

Shen

Foster

2001

Molecular and Cellular Biology

210

198

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In response to epidermal growth factor (EGF), the EGF receptor is endocytosed and degraded. A substantial lag period exists between endocytosis and degradation, suggesting that endocytosis is more than a simple negative feedback. Phospholipase D (PLD), which has been implicated in vesicle formation in the Golgi, is activated in response to EGF and other growth factors. We report here that EGF receptor endocytosis is dependent upon PLD and the PLD1 regulators, protein kinase C ␣ and RalA. EGF-induced receptor degradation is accelerated by overexpression of either wild-type PLD1 or PLD2 and retarded by overexpression of catalytically inactive mutants of either PLD1 or PLD2. EGF-induced activation of mitogen-activated protein kinase, which is dependent upon receptor endocytosis, is also dependent upon PLD. These data suggest a role for PLD in signaling that facilitates receptor endocytosis.Phospholipase D (PLD) is a widely distributed enzyme that hydrolyzes phosphatidylcholine, a major phospholipid in the cell membrane, to form phosphatidic acid (PA) and choline. PLD activity, which can be detected in virtually all cell types as well as in most cellular organelles, is believed to play an important role in the regulation of cell physiology by extracellular signals, such as hormones, neurotransmitters, growth factors, and cytokines (8). Multiple PLD activities have been characterized in mammalian cells, and more recently, two mammalian PLD genes (PLD1 and PLD2) have been cloned (6,11,18,22,30). Recent studies indicate that PLD has many different functions in signal transduction, vesicle trafficking, and cytoskeletal dynamics (21). Vesicle budding in the Golgi network was shown to be mediated in part by Arf family GTPases (35). The discovery that Arf family GTPases regulate PLD activity (3, 5) suggested the possibility that PLD was also involved in vesicle transport. Consistent with this idea, PA formation by PLD-mediated hydrolysis of phosphatidylcholine has been reported to be required for the formation of Golgi vesicles (20) and for the transport of vesicles from the endoplasmic reticulum to the Golgi complex (1). PLD has also been reported to stimulate the release of secretory vesicles from the trans-Golgi network (4). It was therefore proposed that the role that Arf plays in vesicle budding in the Golgi network is to regulate PLD activity and PA production (15,33,34). However, there is controversy on this point (2, 40, 41), and it still is not clear how PLD and its primary metabolite, PA, might contribute to vesicle formation.PLD activity is elevated in response to many extracellular signals (8). Our laboratory has investigated the role PLD plays in the transduction of intracellular signals initiated by epidermal growth factor (EGF) (13,23,38). In response to EGF, the EGF receptor is internalized and then degraded (10). The internalization of the EGF receptor is a process that involves endocytic vesicles (10). Since PLD has been implicated in vesicle formation and membrane traffic as discussed above, we hypothesi...

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Section: Discussionmentioning

confidence: 75%

Section: Fig 2 Egf-induced Receptor Degradation Is Inhibited By Primentioning

confidence: 99%

Role for Phospholipase D in Receptor-Mediated Endocytosis

Shen

Foster

2001

Molecular and Cellular Biology

210

198

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“…Studies with pertussis toxin (PTX) and PKC inhibitors, furthermore, suggested that this potentiation of PLC stimulation by GPCRs is mediated by G i type G proteins and involves activation of a PKC isoenzyme (8,9). Since GPCRs and RTKs activate distinct PLC isoenzymes and by distinct mechanisms, we wondered whether GPCRs may also induce sensitization of PLC stimulation by RTKs endogenously expressed in HEK-293 cells (10,11). We report here that short term activation of GPCRs can induce a long lasting up-regulation of PLC stimulation by EGF and PDGF but not insulin.…”

Section: Stimulation Of Phosphoinositide-hydrolyzing Phospholipase C mentioning

confidence: 79%

G Protein-coupled Receptor-induced Sensitization of Phospholipase C Stimulation by Receptor Tyrosine Kinases

Schmidt

Frings

Mono

et al. 2000

Journal of Biological Chemistry

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Activation of stably expressed M 2 and M 3 muscarinic acetylcholine receptors (mAChRs) as well as of endogenously expressed lysophosphatidic acid and purinergic receptors in HEK-293 cells can induce a long lasting potentiation of phospholipase C (PLC) stimulation by these and other G protein-coupled receptors (GPCRs). Here, we report that GPCRs can induce an up-regulation of PLC stimulation by receptor tyrosine kinases (RTKs) as well and provide essential mechanistic characteristics of this sensitization process. Pretreatment of HEK-293 cells for 2 min with carbachol, a mAChR agonist, lysophosphatidic acid, or ATP, followed by agonist washout, strongly increased (by 2-3-fold) maximal PLC stimulation (measured >40 min later) by epidermal growth factor and platelet-derived growth factor, but not insulin, and largely enhanced PLC sensitivity to these RTK agonists. The up-regulation of RTK-induced PLC stimulation was cycloheximide-insensitive and was observed for up to ϳ90 min after removal of the GPCR agonist. Sensitization of receptor-induced PLC stimulation caused by prior M 2 mAChR activation was fully prevented by pertussis toxin and strongly reduced by expression of G␤␥ scavengers. Furthermore, inhibition of conventional protein kinase C (PKC) isoenzymes and chelation of intracellular Ca 2؉ suppressed the sensitization process, while overexpression of PKC-␣, but not PKC-␤I, further enhanced the M 2 mAChR-induced sensitization of PLC stimulation. None of these treatments affected acute PLC stimulation by either GPCR or RTK agonists. Taken together, short term activation of GPCRs can induce a strong and long lasting sensitization of PLC stimulation by RTKs, a process apparently involving G i -derived G␤␥s as well as increases in intracellular Ca 2؉ and activation of a PKC isoenzyme, most likely PKC-␣. Stimulation of phosphoinositide-hydrolyzing phospholipase C (PLC)1 is a cellular response to activation of a large variety of membrane receptors, including numerous G protein-coupled receptors (GPCRs) as well as several receptor tyrosine kinases (RTKs). These two types of membrane receptors generally stimulate distinct PLC isoenzymes. GPCRs activate PLC-␤ isoenzymes, either via GTP-liganded ␣ subunits of the G q class of G proteins or by ␤␥ dimers liberated from G i type G proteins. In contrast, RTKs, such as those for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), activate PLC-␥ isoenzymes by recruitment of these PLC enzymes to the autophosphorylated RTKs and subsequent tyrosine phosphorylation (1, 2). The hydrolysis of phosphatidylinositol 4,5-bisphosphate by PLC enzymes results in the generation of the two second messengers, inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol, which induce Ca 2ϩ release from intracellular stores and activation of protein kinase C (PKC) isoforms, respectively. It is generally accepted that by these functional consequences stimulation of PLC enzymes plays a major role in many early and late cellular responses to receptor activation, such as smooth m...

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“…For instance, TSC and PLD are both modulated by mitogens (e.g., serum and insulin) [40][41][42][43][44][45][46] and TNFα. 15,47 The Ras-Raf-MEK-Erk pathway inhibits TSC2 via phosphorylation by either Erk 48,49 or a downstream kinase Rsk, 50 at the same time PLD activation by Ras [51][52][53][54] or Erk 54,55 has also been suggested. Most recently, our studies have uncovered a direct interaction between Rheb and PLD1.…”

Section: Pld1 As An Effector Of Rheb In Mtorc1 Signalingmentioning

confidence: 99%