Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain

Rossum, Damian B. van; Patterson, Randen L.; Sharma, Sumit; Barrow, Roxanne K.; Kornberg, Michael D.; Gill, Donald L.; Snyder, Solomon H.

doi:10.1038/nature03340

Cited by 171 publications

(157 citation statements)

References 14 publications

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“…For instance, Y509 and F510 have been shown to be required for an interaction between PLC-␥1 and EF1-␣, and this interaction appears to promote PLC-␥1 activation (3). Furthermore, the PLC-␥1 sPHC domain has been suggested to interact with an sPHN-like domain in the TRPC3 calcium channel to form a full PH domain capable of interacting with phosphoinositides (37). While our data strongly indicate that the sPHN and SH2C domains cooperate in their abilities to maintain PLC-␥1 in an inactive conformation, the precise mechanism responsible for this inhibition is still under investigation.…”

Section: Discussionmentioning

confidence: 52%

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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Section: Discussionmentioning

confidence: 52%

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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“…4D). TRPC channels interact directly with PIP 2 through a conserved lipid-binding domain (29), hence PLC-induced PIP 2 breakdown and DAG production may occur predominantly in the inner bilayer leaflet close to the channel. The small-head group DAG molecule would result in increased membrane stress depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

Spassova

Hewavitharana

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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437

353

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The TRP family of ion channels transduce an extensive range of chemical and physical signals. TRPC6 is a receptor-activated nonselective cation channel expressed widely in vascular smooth muscle and other cell types. We report here that TRPC6 is also a sensor of mechanically and osmotically induced membrane stretch. Pressure-induced activation of TRPC6 was independent of phospholipase C. The stretch responses were blocked by the tarantula peptide, GsMTx-4, known to specifically inhibit mechanosensitive channels by modifying the external lipid-channel boundary. The GsMTx-4 peptide also blocked the activation of TRPC6 channels by either receptor-induced PLC activation or by direct application of diacylglycerol. The effects of the peptide on both stretch-and diacylglycerol-mediated TRPC6 activation indicate that the mechanical and chemical lipid sensing by the channel has a common molecular mechanism that may involve lateral-lipid tension. The mechanosensing properties of TRPC6 channels highly expressed in smooth muscle cells are likely to play a key role in regulating myogenic tone in vascular tissue.GsMTx-4 peptide ͉ mechanosensitivity ͉ tarantula venom ͉ myogenic tone ͉ calcium signals T he superfamily of TRP cation channels transduce a remarkable spectrum of signals ranging from small secondmessenger molecules to physical parameters including temperature, osmolarity, and touch (1, 2). Among the several subfamilies of TRP channels, the TRPC nonselective cation channels activated in response to PLC-coupled receptors are widely expressed among tissues (2, 3). The closely related subgroup comprising TRPC3, TRPC6, and TRPC7 channels are directly activated by diacylglycerol through a PKC-independent mechanism (3, 4). TRPC6 channels are highly expressed in a number of different tissues including vascular smooth muscle cells (5-8). Despite their abundance, the exact physiological role of TRPC6 channels has not been elucidated. Recently it has been suggested that TRPC6 channels are involved in hemodynamic regulation (6, 9) and may play a role in generating myogenic tone in response to intravascular pressure in arteries (6, 9). This is a key mechanism to control blood flow in arteries and arterioles (10, 11) involving depolarization, activation of Ca 2ϩ entry, and the contraction of vascular smooth muscle cells (11). Increases in Ca 2ϩ in response to pressure not only activate smooth muscle cell contraction but also modify their growth and differentiation (12). However, the identity and gating mechanisms of the mechanical sensors that mediate the depolarizing response have not been identified.TRPC6 channels are expressed predominantly in cells responding to hydrostatic pressure changes including vascular smooth muscle and glomerular podocytes and have been implicated in mediating pressure-induced responses (6, 13). TRPC6 channels mediate receptor-induced depolarization in smooth muscle cells (7,9), and opening of the related TRPC1 channel has been shown to be activated by stretch (14). In addition to being implicated in ...

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“…Interestingly, both PLC␥ isoforms have been shown to mediate agonist-induced Ca 2ϩ entry, at least in part by a phospholipase C activity-independent manner (59,70). Very recent evidence suggests that PH-c of PLC␥ 1 controls cell surface expression of the canonical transient receptor potential channel 3 (TRPC3) by interacting with a complementary partial PH-like domain present within its amino-terminal portion (71). Whether activated Rac GTPases mediate translocation of TRP channels to the plasma membrane via PLC␥ 2 remains an intriguing question to be clarified by future experimentation, in particular since there is precedence for an enhancement of rapid vesicular translocation and insertion of TRP channels by activated Rac1 (72).…”

Section: Discussionmentioning

confidence: 99%

Isozyme-specific Stimulation of Phospholipase C-γ2 by Rac GTPases

Piechulek

Rehlen

Walliser

et al. 2005

Journal of Biological Chemistry

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The regulation of the two isoforms of phospholipase C-␥, PLC␥ 1 and PLC␥ 2 , by cell surface receptors involves protein tyrosine phosphorylation as well as interaction with adapter proteins and phosphatidylinositol 3,4,5-trisphosphate (PtdInsP 3 ) generated by inositol phospholipid 3-kinases (PI3Ks). All three processes may lead to recruitment of the PLC␥ isozymes to the plasma membrane and/or stimulation of their catalytic activity. Recent evidence suggests that PLC␥ may also be regulated by Rho GTPases. In this study, PLC␥ 1 and PLC␥ 2 were reconstituted in intact cells and in a cell-free system with Rho GTPases to examine their influence on PLC␥ activity. PLC␥ 2 , but not PLC␥ 1 , was markedly activated in intact cells by constitutively active Rac1 G12V , Rac2 G12V , and Rac3 G12V but not by Cdc42 G12V and RhoA G14V . The mechanism of PLC␥ 2 activation was apparently independent of phosphorylation of tyrosine residues known to be modified by PLC␥ 2 -activating protein-tyrosine kinases. Activation of PLC␥ 2 by Rac2 G12V in intact cells coincided with a translocation of PLC␥ 2 from the soluble to the particulate fraction. PLC␥ isozyme-specific activation of PLC␥ 2 by Rac GTPases (Rac1 ≈ Rac2 > Rac3), but not by Cdc42 or RhoA, was also observed in a cell-free system. Herein, activation of wild-type Rac GTPases with guanosine 5-(3-O-thio)triphosphate caused a marked stimulation of PLC␥ 2 but had no effect on the activity of PLC␥ 1 . PLC␥ 1 and PLC␥ 2 have previously been shown to be indiscriminately activated by PtdInsP 3 in vitro. Thus, the results suggest a novel mechanism of PLC␥ 2 activation by Rac GTPases involving neither protein tyrosine phosphorylation nor PI3K-mediated generation of PtdInsP 3 .Inositol phospholipid-specific phospholipases C (PLCs) 3 catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ) to produce inositol 1,4,5-trisphosphate and diacylglycerol. While the products of this reaction have long been known to act as intracellular second messengers (reviewed in Refs. 1-4), it has only recently become clear that the phospholipid substrate itself may also be considered an intracellular signaling molecule in that its local concentration in the plasma membrane and possibly in other cellular membranes regulates the activities and/or subcellular distribution of a number of regulatory or structural proteins. These include enzymes, ion channels and transporters, transcription factors, scaffolding proteins, cytoskeletal proteins, as well as proteins involved in the regulation of exocytosis, endocytosis, and membrane trafficking (reviewed in Refs. 5-8).The mammalian PLCs are divided into six subfamilies, designated ␤, ␥, ␦, ⑀, , and (reviewed in Refs. 9 and 10). The four members of the PLC␤ subfamily are activated by ␤␥ dimers of heterotrimeric G proteins and/or members of the ␣ q subfamily of G protein ␣ subunits and by certain Rho GTPases (11-14). The two members of the PLC␥ family are activated by receptor and nonreceptor protein-tyrosine kinases (reviewed in Refs. 9, 10, 15, ...

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Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain

Cited by 171 publications

References 14 publications

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

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

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

Isozyme-specific Stimulation of Phospholipase C-γ2 by Rac GTPases

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