Stimulation of Phospholipase C-γ1 Membrane Association by Epidermal Growth Factor

Todderud, Gordon; Wahl, Matthew I.; Rhee, Sue Goo; Carpenter, Graham

doi:10.1126/science.2374928

Cited by 151 publications

(74 citation statements)

References 25 publications

(29 reference statements)

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“…Importantly, growth factor-stimulation not only induces receptor association but also translocation of PLC-γ1 from the cytosol to the membrane (Todderud et al, 1990). Until now, the driving force behind this translocation remains unknown, but it is suspected that the membrane-targeting is linked to growth factor receptors.…”

Section: Activation Of Plc-γ γ γ γ1mentioning

confidence: 99%

“…However, recently, it has been reported that the C-terminal SH2 domain of PLC-γ1 is involved in interactions with synaptojanin (Ahn et al, 1998), the actin-cytoskeleton (Pei et al, 1996), PIP 3 (Bae et al, 1998;Rameh et al, 1998) and FAK (Zhang et al, 1999). These observations suggest that the two SH2 domains of PLC-γ1 are dissimilar and may mediate the recognition of specific phosphorylation sites.Importantly, growth factor-stimulation not only induces receptor association but also translocation of PLC-γ1 from the cytosol to the membrane (Todderud et al, 1990). Until now, the driving force behind this translocation remains unknown, but it is suspected that the membrane-targeting is linked to growth factor receptors.…”

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The mechanism of phospholipase C-γ1 regulation

Kim

Kim²,

Ryu³

et al. 2000

Exp Mol Med

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OverviewPhospholipase C (PLC) 1 hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate the second messengers, inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 induces a transient increase in intracellular free Ca 2+ , while DAG directly activates protein kinase C. Upon stimulation of cells with growth factors, PLC-γ γ γ γ1 is activated upon their association with and phosphorylation by receptor and non-receptor tyrosine kinases. In this review, we will focus on the activation mechanism and regulatory function of PLC-γ γ γ γ1.Keywords: phospholipase C, protein kinase C IntroductionPhosphoinositide-specific phospholipase C (PLC) plays a pivotal role in transmembrane signaling. In response to various extracellular stimuli, such as hormones, growth factors, and neurotransmitters, PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP 3 ). IP 3 induces a transient increase in intracellular free Ca 2+ , while DAG is a direct activator of protein kinase C (PKC) (Nishizuka, 1986;Berridge and Irvine, 1989). These processes have been implicated in many cellular physiological functions, such as secretion, cell proliferation, cell growth and differentiation (Rana and Hokin, 1990). In spite of low overall homology in the predicted amino acid sequences of the multiple PLCisozymes, there are significant sequence similarities in two domains which are designated as the X-and Ydomain (Noh et al., 1995;Rhee and Bae, 1997; Sekiyama et al., 1999). So far, ten mammalian PLC-isozymes have been characterized at the cDNA level; they can be subdivided into three types (β, γ, δ) on the basis of relative locations of the X-and Y-domains in the primary structure (Noh et al., 1995;Rhee and Bae, 1997). The β type includes four PLCs (PLC-β1 through PLC-β4), the γ type includes two PLCs (PLC-γ1 and PLC-γ2), and the δ type includes four enzymes (PLC-δ1 through PLC-δ4) (Suh et al., 1988;Noh et al., 1995;Rhee and Bae, 1997) ( Figure 1). The existence of multiple forms of PLC enzymes suggests that each isozyme may differ in some respect, in tissue distribution, intracellular localization, regulatory mechanisms, and other downstream functions. Emerging evidence suggests that an additional level of diversity may exist beyond the above subgroup classification, because individual genes may yield multiple PLC products due to alternative splicing of the mRNA (Bahk et al., 1994;Kim et al., 1998). The diversity among the PLC enzymes point to selective coupling of individual PLCs to different receptors and signaling pathways. However, very little is known about the identity of the specific signaling pathways for each isozymes or how each isozymes function in vivo. Although PLC enzymes have been purified and extensively characterized biochemically, their function in vivo remains to be clarified.The catalytic activities of the PLC-β type isozymes in vivo are mediated by α-and βγ subunits of heterotrimeric G-proteins (Smrcka et al., 1991;...

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Section: Activation Of Plc-γ γ γ γ1mentioning

confidence: 99%

mentioning

confidence: 99%

The mechanism of phospholipase C-γ1 regulation

Kim

Kim²,

Ryu³

et al. 2000

Exp Mol Med

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“…In quiescent cells, cytosolic sequestration of PLC-␥1 limits access to PI(4,5)P 2 in the plasma membrane. Cell stimulation induces membrane recruitment of PLC-␥1 and its tyrosine phosphorylation, essential steps in PLC-␥1 activation (2,23,36). Key components of PLC-␥ that are involved in these activation events are located within a region unique to PLC-␥ between the X and Y portions of the catalytic domain.…”

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Intramolecular Regulation of Phospholipase C-γ1 by Its C-Terminal Src Homology 2 Domain

DeBell

Graham

Reischl

et al. 2007

Molecular and Cellular Biology

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Phosphoinositide-specific phospholipase C-␥1 (PLC-␥1) is a key enzyme that governs cellular functions such as gene transcription, secretion, proliferation, motility, and development. Here, we show that PLC-␥1 is regulated via a novel autoinhibitory mechanism involving its carboxy-terminal Src homology (SH2C) domain. Mutation of the SH2C domain tyrosine binding site led to constitutive PLC-␥1 activation. The amino-terminal split pleckstrin homology (sPHN) domain was found to regulate the accessibility of the SH2C domain. PLC-␥1 constructs with mutations in tyrosine 509 and phenylalanine 510 in the sPHN domain no longer required an intact amino-terminal Src homology (SH2N) domain or phosphorylation of tyrosine 775 or 783 for activation. These data are consistent with a model in which the SH2C domain is blocked by an intramolecular interaction(s) that is released upon cellular activation by occupancy of the SH2N domain.Phosphoinositide-specific phospholipase C-␥1 (PLC-␥1) is activated in response to ligand binding by a variety of receptors (2). PLC-␥1 hydrolyzes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ], leading to the generation of the second messengers, inositol triphosphate (IP 3 ) and diacylglycerol, which release Ca 2ϩ from intracellular stores and activate Ras through the RasGRP/protein kinase C pathway, respectively (8, 13). PLC-␥1 has also been shown to play a role in the activation of NF-B (7). These pathways in turn initiate signaling cascades that culminate in cytokine production, activation of effector function, and cell proliferation (2, 5). The central role of PLC-␥1 in cellular function is further illustrated by the fact that inactivation of the PLC-␥1 gene in mice is embryonic lethal (16).Regulation of PLC-␥1 activity is complex. In quiescent cells, cytosolic sequestration of PLC-␥1 limits access to PI(4,5)P 2 in the plasma membrane. Cell stimulation induces membrane recruitment of PLC-␥1 and its tyrosine phosphorylation, essential steps in PLC-␥1 activation (2,23,36). Key components of PLC-␥ that are involved in these activation events are located within a region unique to PLC-␥ between the X and Y portions of the catalytic domain. This area is composed of two Src homology 2 (SH2) domains and an Src homology 3 (SH3) domain. The N-terminal SH2 domain (SH2N) is critical for binding to either tyrosine-phosphorylated receptor kinases or adaptor molecules that mediate PLC-␥1 relocation to the plasma membrane (6,14,25). The function of the C-terminal SH2 domain (SH2C) is less clear but is also essential for PLC-␥1 activation (1, 6, 14, 33). Interestingly, the tyrosine residues that are essential for PLC-␥1 activity (Y775 and Y783 in PLC-␥1 and Y753 and Y759 in PLC-␥2) are also located in this region (29,30).Components of the SH region not only are essential for PLC-␥1 activation but also may participate in its autoregulation. The individual X or Y elements of the catalytic domain alone are inactive. When mixed together in vitro, the hydrolytic activity of the combined X and Y elements was found...

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“…PLC γ appears to be regulated by tyrosine phosphorylation in response to growth factor receptor occupancy [5]. The phosphorylation of PLC γ does not affect the kinetic properties of the enzyme, but causes a redistribution of the enzyme from the cytosol to cell membrane [6,7]. Tyrosine phosphorylation of PLC γ promotes its association with actin components of the cytoskeleton [8,9].…”

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Localization of phospholipase C δ3 in the cell and regulation of its activity by phospholipids and calcium

Pawełczyk

Matecki

1998

European Journal of Biochemistry

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The localization of phospholipase C δ3 (PLC δ3) in the cell and its regulatory properties has been investigated. Western blotting showed that human platelet PLC δ3 is located in the membrane and cytosolic fraction. The enzyme amount in the cytosolic fraction was significantly lower than that in the membrane fraction. In rat liver, PLC δ3 was present in both the membrane and cytosolic fraction and was absent in nuclei. Examination of the effects of phospholipids on PLC δ3 revealed that this enzyme is inhibited by phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho). Similar inhibition was observed in the presence of sphingomyelin and phosphatidylserine (PtdSer). This is in contrast to PLC δ1, which is activated by PtdCho and PtdEtn. In a detergent assay, PLC δ1 is activated by spermine and sphingosine, whereas PLC δ3 was inhibited by both these compounds at concentrations that maximally stimulated PLC δ1. A deletion mutant of PLC δ3, lacking the entire pleckstrin homology (PH) domain (residues 1Ϫ137), was fully active in the detergent assay, and it was inhibited by spermine, sphingosine and phospholipids to the same extent as the native enzyme. PLC δ3 activation required calcium ions. The relationship between the Ca 2ϩ concentration and enzymatic activity was almost identical for the deletion mutant and the native enzyme. However, in the liposome assay, PLC δ3 was less sensitive to Ca 2ϩ stimulation. This is in contrast to PLC δ1, which is equally sensitive to Ca 2ϩ stimulation in both the detergent and liposome assays. We conclude that Ca 2ϩ is necessary to induce specific conformational changes of PLC δ3, which leads to a productive orientation of the catalytic domain relative to the membrane. The regulatory properties of PLC δ3 described in this report suggest that PLC δ3 has a relatively low activity in cellular conditions that fully activate PLC δ1.Keywords : phospholipase C δ3; platelets; localization; phospholipids ; calcium.Phospholipase C (PLC) hydrolyzes phosphatidylinositol located in cellular membranes to generate diacylglycerol and inositol 1,4,5-triphosphate (InsP 3 ). Diacylglycerol activates protein kinase C and InsP 3 mobilizes Ca 2ϩ from intracellular stores [1,2]. Changes in Ca 2ϩ and diacylglycerol levels affect virtually every aspect of cellular regulation directly or indirectly. The control of PLC activity is thus one of the major starting points for cellular regulation.To date, three major types of phosphoinositide-specific phospholipase C species named β, γ and δ, have been characterized [3,4]. Each type of PLC is regulated differently. PLC γ appears to be regulated by tyrosine phosphorylation in response to growth factor receptor occupancy [5]. The phosphorylation of PLC γ does not affect the kinetic properties of the enzyme, but causes a redistribution of the enzyme from the cytosol to cell membrane [6,7]. Tyrosine phosphorylation of PLC γ promotes its association with actin components of the cytoskeleton [8,9]. PLC β isozymes are activated by the A and βγ subunits of the h...

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Stimulation of Phospholipase C-γ1 Membrane Association by Epidermal Growth Factor

Cited by 151 publications

References 25 publications

The mechanism of phospholipase C-γ1 regulation

The mechanism of phospholipase C-γ1 regulation

Intramolecular Regulation of Phospholipase C-γ1 by Its C-Terminal Src Homology 2 Domain

Localization of phospholipase C δ3 in the cell and regulation of its activity by phospholipids and calcium

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