HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Summary Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Related articles in MI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wing, M. R. Articles by Harden, T. K. Search for Related Content PubMed PubMed Citation Articles by Wing, M. R. Articles by Harden, T. K.

PLC-: A Shared Effector Protein in Ras-, Rho-, and Gß-Mediated Signaling

Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599

Correspondence: Address correspondence to TKH. E-mail tkh{at}med.unc.edu; fax 919-966-5640.

	SUMMARY

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
The conceptual segregation of G protein–stimulated cell signaling responses into those mediated by heterotrimeric G proteins versus those promoted by small GTPases of the Ras superfamily is no longer vogue. PLC- , an isozyme of the phospholipase C (PLC) family, has been identified recently and dramatically extends our understanding of the crosstalk that occurs between heterotrimeric and small monomeric GTPases. Like the widely studied PLC-ß isozymes, PLC- is activated by Gß released upon activation of heterotrimeric G proteins. However, PLC- markedly differs from the PLC-ß isozymes in its capacity for activation by G_12/13 - but not G_q -coupled receptors. PLC- contains two Ras-associating domains located near the C terminus, and H-Ras regulates PLC- as a downstream effector. Rho also activates PLC- , but in a mechanism independent of the C-terminal Ras-associating domains. Therefore, Ca²⁺ mobilization and activation of protein kinase C are signaling responses associated with activation of both H-Ras and Rho. A guanine nucleotide exchange domain conserved in the N terminus of PLC- potentially confers a capacity for activators of this isozyme to cast signals into additional signaling pathways mediated by GTPases of the Ras superfamily. Thus, PLC- is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways.

	INTRODUCTION

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
Two decades ago, Robert Michell (1, 2) , Michael Berridge (3) , and their colleagues discovered the role of phospholipase C (PLC) in initiating the intracellular events elicited by many hormones, neurotransmitters, and growth factors. Delineation of the enzymatic hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂ ] by PLC as the first of many biochemical steps underlying both the mobilization of intracellular Ca²⁺ and activation of protein kinase C (Figure 1) paved the way for understanding signaling pathways that emanate from activation of other lipid-metabolizing enzymes (e.g., phospholipase A₂ , phospholipase D, and phosphoinositol 3-kinase).

View larger version (25K): [in this window] [in a new window]   Figure 1. Receptor-promoted activation of phospholipase C and generation of second messengers. A prototypical G protein–coupled receptor is schematized as a black string (left) with seven transmembrane domains. Binding of a hormone ligand (gray oval) results in activation and dissociation of heterotrimeric G proteins into free Gß and GTP-bound subunits. In accordance with the historical view, the GTP-bound subunit activates an isoform of PLC-ß, which hydrolyzes phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] into inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which raises the cytosolic concentration of calcium ions ([Ca2+]i) and diacylglycerol (DAG), an activator of protein kinase C (PKC). Also schematized is a receptor tyrosine kinase (right) bound by an extracellular growth factor (pink circle); the epidermal growth factor receptor (EGFR) conforms to this schematization. Traditionally, this second class of receptor was proposed to initiate an inositol lipid response through activation of an isoform of PLC- as a consequence of tyrosine phosphorylation of the isozyme.

Our conception of G protein–mediated regulation of inositol lipid signaling has been dramatically altered by the recent discovery of a new PLC isozyme, PLC- (17–20) . This G protein effector is dually regulated upstream by small monomeric GTPases of the Ras (18, 20) and Rho (21) families and by heterotrimeric G proteins (19, 22) . Moreover, downstream signal(s) in addition to the mobilization of Ca²⁺ and activation of protein kinase C emanate from the activity of PLC- as a guanine nucleotide exchange factor (GEF) for GTPases of the Ras superfamily (18, 19, 23, 24) . Thus, upstream signals from small monomeric GTPases as well as those from heterotrimeric G proteins converge on PLC- , and multiple downstream signals emanate from PLC- . We discuss here the current understanding of this pivotal signaling protein.

	IDENTIFICATION OF PLC-

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
Kataoka and his colleagues (17) identified a C. elegans protein, PLC210, in a yeast two-hybrid screen to identify proteins that bind LET-60 (i.e., a C. elegans Ras ortholog). This 210-kDa (1898-residue) protein possesses sequences that are homologous to the catalytic domain (i.e., the X and Y boxes) and the Ca²⁺ /lipid-binding domain (i.e., the C2 domain) that typify all characterized PLCs. Moreover, the unique presence of a C-terminal Ras-associating (RA) domain and an N-terminal Ras GEF domain suggested a bifunctional regulatory potential for PLC- as both an effector of Ras and an activator of downstream Ras GTPase signaling pathways.

Three laboratories independently applied sequence information from existing expressed sequence tag databases to clone mammalian orthologs of PLC210, designated PLC- (18–20) . Two human splice variants of 1994 and 2303 residues, which differ only in their N termini, and a single rat isoform of 2281 residues were reported. Further examination of databases suggests the existence of additional splice variants of human PLC- . The mammalian isoforms exhibit a domain organization similar to the C. elegans ortholog (Figure 2). The functionally characterized domains of PLC- are considered below.

View larger version (22K): [in this window] [in a new window]   Figure 2. Domain organization and amino acid sequence comparisons among human PLC isozymes. A. The five classes of phospholipase C isoforms are distinguished by differing structural domains, drawn here to relative scale in the full-length isozymes. The unique 60–70-residue "insert" is identified in the PLC- Y box. B. A dendogram of the five groups of PLC isoforms is presented. The classification of PLC isoforms into five groups is reflected at the overall sequence level. (Domain identification: Cys, cysteine-rich region; CDC25, guanine nucleotide exchange domain conserved among guanine nucleotide exchange factors (GEF); PH, pleckstrin homology domain; EF, EF-hand domain; X and Y, core catalytic domains (i.e., a TIM barrel); C2, Ca2+/lipid-binding domain; RA1 and RA2, Ras-associating domains. Genbank protein accession numbers for the known human PLC isozymes are as follows: PLC-, [1994 aa] AAG28341, [2303 aa] AAG17145; PLC-ß1, Q9NQ66; PLC-ß2, Q00722; PLC-ß3, Q01970; PLC-ß4, Q15147; PLC-1, P19174; PLC-2, P16885; PLC-1, P51178; PLC-3, NP_588614; PLC-4, NP_116115; PLC-, NP_149114.)

	RAS-ASSOCIATING DOMAINS

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

PLC- expressed ectopically in Cos-7 cells undergoes translocation from the cytosol to the plasma membrane when co-expressed with a mutant form of H-Ras deficient in GTPase activity, and to perinuclear compartments such as the Golgi apparatus when co-expressed with Rap1A (18) . Activation of the epidermal growth factor receptor on cells expressing either H-Ras or Rap1A results in membrane recruitment of GEFs, formation of H-Ras•GTP and Rap1A•GTP, and translocation of PLC- to either the plasma membrane in H-Ras–expressing cells or to the Golgi apparatus in Rap1A-expressing cells.

Co-expression of PLC- with a constitutively active mutant of H-Ras increases the rate of inositol lipid hydrolysis in Cos-7 cells (20) . This effect is attenuated by deletion of either the RA1 or RA2 domain, by mutation of RA2 (e.g., K2150E), or by mutations of H-Ras in its effector-binding domain. H-Ras•GTP activates (greater than twofold) purified PLC- in experiments with reconstituted liposomes (18) . Although the mechanism for H-Ras activation of PLC- is not clear, one interpretation of these studies is that H-Ras increases the phospholipase activity of PLC- by promoting the recruitment of the enzyme to the plasma membrane, that is, to the location of PtdIns(4,5)P₂ substrate. The potential interplay between the RA domains and the GEF activity of the CDC25 domain (see below) has not been explored.

	CDC25 DOMAIN

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
Proteins that contain CDC25 domains generally act as GEFs for Ras-family GTPases, and in many instances, CDC25 domains confer specificity for particular members of the Ras family (28) . Therefore, the discovery of a CDC25 domain near the N terminus of PLC- is highly intriguing (17–20) . The expression of PLC- in TSA201 cells promotes formation of GTP•H-Ras (19) . Moreover, PLC- containing a single amino acid substitution (H1144L) that obliterates phospholipase activity nevertheless retains the capacity to function as a GEF, promoting formation of GTP•H-Ras. Indeed, the H1144L mutant of PLC- , like the wild-type enzyme and the GEF domain isolated from the wild-type enzyme, possesses the capacity to activate the mitogen-activated protein kinase pathway in a manner dependent on Ras but independent of PtdIns(4,5)P₂ hydrolysis (19) .

In contrast to the results of Lopez et al. (19) , Jin and colleagues (23) report that the CDC25 domain of PLC- exhibits GEF activity toward Rap1 but not to other Ras-family GTPases such as H-Ras and Rap2. Purified full-length PLC- , or an N-terminal fragment of PLC- that includes the CDC25 domain (PLC- CDC25), increases the rate of GDP release from Rap1A, whereas a C-terminal fragment of PLC- (PLC- N) has no effect. Similarly, co-expression of Rap1A with either full-length PLC- or PLC- CDC25 (but not with PLC- N) in Cos-7 cells increases intracellular levels of Rap1A•GTP and results in activation of the downstream kinases B-Raf and extracellular signal–regulated kinase (ERK). Intracellular levels of activated Raf-1 kinase are unchanged in cells expressing PLC- and either H-Ras or Rap1A. Furthermore, epidermal growth factor induces the sustained translocation of PLC- to perinuclear compartments, such as the Golgi apparatus, in cells that express Rap1A, whereas PLC- lacking the CDC25 domain is only transiently translocated to these compartments (23) . These observations suggest a prominent role for the CDC25 domain of PLC- in amplifying Rap1-promoted signaling.

The quantification of PLC- –promoted inositol lipid hydrolysis and Ca²⁺ mobilization in response to growth factor receptor activation in Cos-7 cells is complicated by the presence of PLC- , which is markedly stimulated by these receptors. Therefore, to explore the molecular basis of Rap1- and H-Ras–mediated regulation of PLC- , Song and coworkers used platelet-derived growth factor (PDGF) to stimulate cells expressing a PDGF receptor mutant incapable of activating PLC- (24) . Persistent PDGF-promoted activation of ectopically expressed PLC- was observed, manifesting a rapid initial phase of activation mediated by Ras and a prolonged phase promoted by Rap1. The CDC25 domain, which exhibits GEF activity toward Rap1 but not H-Ras, was critical for the prolonged activation of PLC- . Interestingly, PDGF prevented apoptosis in BaF3 hematopoietic cells containing the mutant receptor and enabled these cells to proliferate in a PLC- –dependent manner. These observations are consistent with a critical role of PLC- for survival and growth of BaF3 cells.

	CORE CATALYTIC DOMAINS (PH, EF, XY, C2)

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
Regulation of inositol lipid signaling by GPCRs had been assumed to arise entirely from the activation of PLC-ß isozymes by G subunits of the G_q family, and in some cases, by Gß generated from other G protein heterotrimers. However, observations that constitutively active G₁₂ (19) and G₁₃ (22) , but not G_q , enhance the phospholipase activity of PLC- alter this dogma. PLC- truncation mutants lacking the CDC25, pleckstrin homology (PH), and RA domains retain the capacity to be activated by G₁₂ and G₁₃ (21) . Therefore, G -promoted activation of PLC- occurs through a mechanism involving the core catalytic region (i.e., EF hands, X and Y boxes, and C2 domain) of the isozyme (Figure 3). Whether the G_12/13 -mediated activation of PLC- requires direct interaction of G and PLC- has not yet been determined.

View larger version (28K): [in this window] [in a new window]   Figure 3. PLC- : A nexus for heterotrimeric and small G protein signaling pathways. Phospholipase C activity of PLC- is stimulated by G12/13, Gß, and activated members of Ras and Rho small GTPases to yield downstream second messengers Ins(1,4,5)P3 and diacylglycerol. In addition, ERK signaling pathways are propagated as a result of the guanine nucleotide exchange activity of the PLC- CDC25 domain. A positive feedback loop is schematized in which CDC25-promoted activation of H-Ras and/or Rap1A in turn activates the lipase activity of PLC- upon binding the C-terminal RA domains (dashed line). See text for details. (AC, adenylyl cyclase; Shc, SH2 domain–containing adaptor protein; IRS, insulin receptor substrate; Grb2, growth factor receptor–bound protein 2; Sos, son of sevenless GEF; MEK, mitogen-activated protein kinase kinase.)

G₁₂ and G₁₃ share the capacity to activate Rho GEFs (i.e., p115RhoGEF, LARG, PDZ-RhoGEF) (29–32) , and therefore, both G₁₂ and G₁₃ activate Rho (33) . Although no data exist that rule out direct interaction of G₁₂ and G₁₃ with PLC- , we hypothesize that G₁₂ - and G₁₃ -mediated activation occurs through an intervening molecule, Rho. This speculation is supported by loss of both Rho and G_12/13 -mediated regulation upon removal of the unique 60–70-residue sequence found in the catalytic core of PLC- but not other PLC isozymes (21) . Preliminary studies from our laboratory have revealed that C3 toxin, which ADP-ribosylates and inactivates Rho, prevents G_12/13 -mediated activation of PLC- but has little effect on G_q activation of PLC-ß isozymes.

Both PH and EF-hand domains exist near the N terminus of PLC- (22) . The known interaction of Gß with the PH domains of other proteins (34, 35) prompted an examination of the capacity of Gß to activate PLC- . Indeed, expression of Gß₁₂ in Cos-7 cells markedly stimulates the enzymatic activity of PLC- (22) ; activation is also observed with other combinations of Gß and G (e.g., Gß₁₃ and Gß₂₂ ). The Gß -promoted stimulation of PLC- is blocked by cotransfection with either of two Gß -interacting proteins, namely, G_i1 and the C terminus of G protein receptor kinase 2. Whether the activation of PLC- by Gß occurs by a direct interaction is not known. Pharmacological inhibition of phosphoinositide 3-kinase does not prevent activation of PLC- by Gß . Similarly, a mutation in the RA2 domain of PLC- that precludes activation by Ras fails to alter the stimulatory activity of Gß₁₂ . Although Gß is known to interact with certain PH domains, truncation mutants of PLC- lacking the PH and CDC25 domains retain Gß -regulated activity.

	REGULATION OF PLC- THROUGH GS

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
Schmidt and coworkers (36, 37) describe a mechanism through which G_s -coupled GPCRs potentially regulate PLC- . EPAC (for e xchange p rotein a ctivated by c AMP), a Rap-specific GEF, potentiates the inositol trisphosphate and Ca²⁺ responses to GPCR stimulation by catecholamines and prostaglandins. Therefore, these investigators examined the roles of Rap GTPases and PLC- in G_s -coupled GPCR signaling. Dominant negative forms of Rap1A, 1B, 2A, and 2B, as well as a dominant negative form of H-Ras, were expressed in HEK-293 cells with the goal of blocking Ins(1,4,5)P₃ accumulation in response to ß -adrenergic receptor stimulation. The dominant negative form of Rap2B, but not the other dominant negative constructs, inhibited the isoproterenol- and forskolin-promoted formation of Ins(1,4,5)P₃ . GTP-dependent binding of Rap2B to PLC- RA2 has been demonstrated (24) , and thus, cyclic AMP–promoted activation of PLC- conceivably occurs through activation of Rap2B and interaction with the RA2 domain (Figure 3).

	CONCLUSION

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 
The observations made by Cantley and coworkers (38) and Wakelam et al. (39) nearly twenty years ago suggested important roles for Ras in the regulation of PtdIns(4,5)P₂ signaling. Recent revelations in the study of the novel PLC isozyme, PLC- , have resurrected this notion and opened a broad set of questions for researchers in the increasingly integrated fields of heterotrimeric and small G protein signaling. The dogma that signaling through heterotrimeric G proteins and through members of the Ras superfamily of small GTPases occurs in a linear and unidirectional fashion thus continues to be refined by the realization that significant crosstalk occurs between these complex signaling pathways.

PLC- exhibits unique regulatory potential as both an initiator and recipient of activated G protein signals. A positive feedback loop also may operate through the isozyme in which H-Ras and/or Rap become GTP-bound through interaction with the CDC25 domain and subsequently activate the phospholipase activity of PLC- via interaction with the RA2 domain, enabling long-lasting signal maintenance. Given these unique signaling attributes and wide tissue distribution of PLC- –encoding mRNA, we assume PLC- subserves critical roles in mammalian physiology. PLC- is well placed to function in the regulation of cell morphology, development, and proliferation, and in this way most assuredly merits attention as a potential therapeutic target.

Ken Harden, Ph.D. (left), is Kenan Professor of Pharmacology at the University of North Carolina School of Medicine. David Bourdon, Ph.D. (middle), and Michele Wing, Ph.D. (right), are postdoctoral fellows in the Department of Pharmacology at the University of North Carolina.

	References

TOP Summary Introduction Identification of PLC... Ras-Associating Domains CDC25 Domain Core Catalytic Domains (PH,... Regulation of PLC-{varepsilon}... Conclusion References

 

1. Michell, R.H. Inositol phospholipids and cell surface receptor function. Biochim. Biophys. Acta 415 , 81–47 (1975).[Medline]
2. Michell, R.H., Kirk, C.J., Jones, L.M., Downes, C.P., and Creba, J.A. The stimulation of inositol lipid metabolism that accompanies calcium mobilization in stimulated cells: Defined characteristics and unanswered questions. Philos. Trans. R. Soc. Lond B Biol. Sci. 296 , 123–138 (1981).[Medline]
3. Berridge, M.J. and Irvine, R.F. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312 , 315–321 (1984).[CrossRef][Medline]
4. Rhee, S.G. Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem. 70 , 281–312 (2001).[CrossRef][Medline]
5. Smrcka, A.V., Hepler, J.R., Brown, K.O., and Sternweis, P.C. Regulation of polyphosphoinositide-specific phospholipase C by purified G_q . Science 251 , 804–807 (1991).[Abstract/Free Full Text]
6. Taylor, S.J., Chae, H.Z., Rhee, S.G., and Exton, J.H. Activation of the ß 1 isozyme of phospholipase C by -subunits of the Gq class of G-proteins. Nature 350 , 516–518 (1991).[CrossRef][Medline]
7. Waldo, G.L., Boyer, J.L., Morris, A.J., and Harden, T.K. Purification of an AlF4- and G-protein beta gamma-subunit-regulated phospholipase C-activating protein. J. Biol. Chem. 266 , 14217–14225 (1991).[Abstract/Free Full Text]
8. Wu, D.Q., Lee, C.H., Rhee, S.G., and Simon, M.I. Activation of phospholipase C by the alpha subunits of the Gq and G11 proteins in transfected Cos-7 cells. J. Biol. Chem. 267 , 1811–1817 (1992).[Abstract/Free Full Text]
9. Camps, M., Carozzi, A., Schnabel, P., Scheer, A., Parker, P.J., and Gierschik, P. Isozyme-selective stimulation of phospholipase C-ß 2 by G protein ß -subunits. Nature 360 , 684–686 (1992).[CrossRef][Medline]
10. Boyer, J.L., Waldo, G.L., and Harden, T.K. ß -Subunit activation of G-protein-regulated phospholipase C. J. Biol. Chem. 267 , 25451–25456 (1992).[Abstract/Free Full Text]
11. Blank, J.L., Brittain, K.A., and Exton, J.H. Activation of cytosolic phosphoinositide phospholipase C by G-protein ß subunits. J. Biol. Chem. 267 , 23069–23075 (1992).[Abstract/Free Full Text]
12. Wahl, M.I., Nishibe, S., Suh, P.-G., Rhee, S.G., and Carpenter, G. Epidermal growth factor stimulates tyrosine phosphorylation of phospholipase C-II independently of receptor internalization and extracellular calcium. Proc. Natl. Acad. Sci. USA 86 , 1568–1572 (1989).[Abstract/Free Full Text]
13. Margolis, B., Rhee, S.G., Felder, S., Mervic, M., Lyall, R., Levitzki, A., Ullrich, A., Zilberstein, A., and Schlessinger, J. EGF induces tyrosine phosphorylation of phospholipase C-II: A potential mechanism for EGF receptor signaling. Cell 57 , 1101–1107 (1989).[CrossRef][Medline]
14. Meisenhelder, J., Suh, P.-G., Rhee, S.G., and Hunter, T. Phospholipase C-c is a substrate for the PDGF and EGF receptor protein tyrosine kinases in vivo and in vitro. Cell 57 , 1099–1122 (1989).
15. Saunders, C.M., Larman, M.G., Parrington, J., Cox, L.J., Royse, J., Blayney, L.M., Swann, K., and Lai, F.A. PLC zeta: A sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development. Development 129 , 3533–3544 (2002).[Abstract/Free Full Text]
16. Cox, L.J., Larman, M.G., Saunders, C.M., Hashimoto, K., Swann, K., and Lai, F.A. Sperm phospholipase Czeta from humans and cynomolgus monkeys triggers Ca2+ oscillations, activation and development of mouse oocytes. Reproduction. 124 , 611–623 (2002).[Abstract]
17. Shibatohge, M., Kariya, K., Liao, Y., Hu, C.D., Watari, Y., Goshima, M., Shima, F., and Kataoka, T. Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras. J. Biol. Chem. 273 , 6218–6222 (1998).[Abstract/Free Full Text]
18. Song, C., Hu, C.D., Masago, M., Kariyai, K., Yamawaki-Kataoka, Y., Shibatohge, M., Wu, D., Satoh, T., and Kataoka, T. Regulation of a novel human phospholipase C, PLC , through membrane targeting by Ras. J. Biol. Chem. 276 , 2752–2757 (2001).[Abstract/Free Full Text]
19. Lopez, I., Mak, E.C., Ding, J., Hamm, H.E., and Lomasney, J.W. A novel bifunctional phospholipase C that is regulated by G 12 and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276 , 2758–2765 (2001).[Abstract/Free Full Text]
20. Kelley, G.G., Reks, S.E., Ondrako, J.M., and Smrcka, A.V. Phospholipase C : A novel Ras effector. EMBO J. 20 , 743–754 (2001).[CrossRef][Medline]
21. Wing, M.R., Snyder, J.T., Sondek, J., and Harden, T.K. Direct activation of Phospholipase C epsilon by Rho. J. Biol. Chem. (in press).
22. Wing, M.R., Houston, D., Kelley, G.G., Der, C.J., Siderovski, D.P., and Harden, T.K. Activation of phospholipase C- by heterotrimeric G protein ß -subunits. J. Biol. Chem. 276 , 48257–48261 (2001).[Abstract/Free Full Text]
23. Jin, T.G., Satoh, T., Liao, Y., Song, C., Gao, X., Kariya, K., Hu, C.D., and Kataoka, T. Role of the CDC25 homology domain of phospholipase C in amplification of Rap1-dependent signaling. J. Biol. Chem. 276 , 30301–30307 (2001).[Abstract/Free Full Text]
24. Song, C., Satoh, T., Edamatsu, H., Wu, D., Tadano, M., Gao, X., and Kataoka, T. Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase C . Oncogene 21 , 8105–8113 (2002).[CrossRef][Medline]
25. Ponting, C.P. and Benjamin, D.R. A novel family of Ras-binding domains. Trends Biochem. Sci. 21 , 422–425 (1996).[CrossRef][Medline]
26. Emerson, S.D., Madison, V.S., Palermo, R.E., Waugh, D.S., Scheffler, J.E., Tsao, K.L., Kiefer, S.E., Liu, S.P., and Fry, D.C. Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface. Biochemistry 34 , 6911–6918 (1995).[CrossRef][Medline]
27. Huang, L., Weng, X., Hofer, F., Martin, G.S., and Kim, S.H. Three-dimensional structure of the Ras-interacting domain of RalGDS. Nat. Struct. Biol. 4 , 609–615 (1997).[CrossRef][Medline]
28. Quilliam, L.A., Rebhun, J.F., and Castro, A.F. A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. Prog. Nucleic Acid Res. Mol. Biol. 71 , 391–444 (2002).[Medline]
29. Kozasa, T., Jiang, X., Hart, M.J., Sternweis, P.M., Singer, W.D., Gilman, A.G., Bollag, G., and Sternweis, P.C. p115 RhoGEF, a GTPase activating protein for G 12 and G 13. Science 280 , 2109–2111 (1998).[Abstract/Free Full Text]
30. Fukuhara, S., Murga, C., Zohar, M., Igishi, T., and Gutkind, J.S. A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho. J. Biol. Chem. 274 , 5868–5879 (1999).[Abstract/Free Full Text]
31. Fukuhara, S., Chikumi, H., and Gutkind, J.S. Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho. FEBS Lett. 485 , 183–188 (2000).[CrossRef][Medline]
32. Suzuki, N., Nakamura, S., Mano, H., and Kozasa, T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc. Natl. Acad. Sci. U. S. A 100 , 733–738 (2003).[Abstract/Free Full Text]
33. Buhl, A.M., Johnson, N.L., Dhanasekaran, N., and Johnson, G.L. G 12 and G 13 stimulate Rho-dependent stress fiber formation and focal adhesion assembly. J. Biol. Chem. 270 , 24631–24634 (1995).[Abstract/Free Full Text]
34. Fushman, D., Najmabadi-Haske, T., Cahill, S., Zheng, J., LeVine, H., III, and Cowburn, D. The solution structure and dynamics of the pleckstrin homology domain of G protein-coupled receptor kinase 2 (beta-adrenergic receptor kinase 1). A binding partner of Gbetagamma subunits. J. Biol. Chem. 273 , 2835–2843 (1998).[Abstract/Free Full Text]
35. Carman, C.V., Barak, L.S., Chen, C., Liu-Chen, L.Y., Onorato, J.J., Kennedy, S.P., Caron, M.G., and Benovic, J.L. Mutational analysis of Gbetagamma and phospholipid interaction with G protein-coupled receptor kinase 2. J. Biol. Chem. 275 , 10443–10452 (2000).[Abstract/Free Full Text]
36. Schmidt, M., Evellin, S., Weernink, P.A., von Dorp, F., Rehmann, H., Lomasney, J.W., and Jakobs, K.H. A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat. Cell Biol. 3 , 1020–1024 (2001).[CrossRef][Medline]
37. Evellin, S., Nolte, J., Tysack, K., vom, D.F., Thiel, M., Weernink, P.A., Jakobs, K.H., Webb, E.J., Lomasney, J.W., and Schmidt, M. Stimulation of phospholipase C- by the M3 muscarinic acetylcholine receptor mediated be cyclic AMP and the GTPase Rap2B . J. Biol. Chem. 277 , 16805–16813 (2002).[Abstract/Free Full Text]
38. Fleischman, L.F., Chahwala, S.B., and Cantley, L. ras-transformed cells: Altered levels of phosphatidylinositol-4,5-bisphosphate and catabolites. Science 231 , 407–410 (1986).[Abstract/Free Full Text]
39. Wakelam, M.J., Davies, S.A., Houslay, M.D., McKay, I., Marshall, C.J., and Hall, A. Normal p21N-ras couples bombesin and other growth factor receptors to inositol phosphate production. Nature 323 , 173–176 (1986).[CrossRef][Medline]

Related articles in MI:

Sites of interest on the World Wide Web - edited by David Siderovski

MI 2003 3: 293. [Full Text]  

This article has been cited by other articles:

				I. Gekel and E. Neher Application of an Epac Activator Enhances Neurotransmitter Release at Excitatory Central Synapses J. Neurosci., August 6, 2008; 28(32): 7991 - 8002. [Abstract] [Full Text] [PDF]

				R. Gbadegesin, B. G. Hinkes, B. E. Hoskins, C. N. Vlangos, S. F. Heeringa, J. Liu, C. Loirat, F. Ozaltin, S. Hashmi, F. Ulmer, et al. Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS) Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1291 - 1297. [Abstract] [Full Text] [PDF]

				H. Chaib, B. E. Hoskins, S. Ashraf, M. Goyal, R. C. Wiggins, and F. Hildebrandt Identification of BRAF as a new interactor of PLC{varepsilon}1, the protein mutated in nephrotic syndrome type 3 Am J Physiol Renal Physiol, January 1, 2008; 294(1): F93 - F99. [Abstract] [Full Text] [PDF]

				P. R. J. Bois A Highly Polymorphic Meiotic Recombination Mouse Hot Spot Exhibits Incomplete Repair Mol. Cell. Biol., October 15, 2007; 27(20): 7053 - 7062. [Abstract] [Full Text] [PDF]

				S. Citro, S. Malik, E. A. Oestreich, J. Radeff-Huang, G. G. Kelley, A. V. Smrcka, and J. H. Brown Phospholipase C{varepsilon} is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation PNAS, September 25, 2007; 104(39): 15543 - 15548. [Abstract] [Full Text] [PDF]

				V. Bertagnolo, M. Benedusi, F. Brugnoli, P. Lanuti, M. Marchisio, P. Querzoli, and S. Capitani Phospholipase C-{beta}2 promotes mitosis and migration of human breast cancer-derived cells Carcinogenesis, August 1, 2007; 28(8): 1638 - 1645. [Abstract] [Full Text] [PDF]

				T. Piechulek, T. Rehlen, C. Walliser, P. Vatter, B. Moepps, and P. Gierschik Isozyme-specific Stimulation of Phospholipase C-{gamma}2 by Rac GTPases J. Biol. Chem., November 25, 2005; 280(47): 38923 - 38931. [Abstract] [Full Text] [PDF]

				J. A. Gollob, C. J. Sciambi, Z. Huang, and H. K. Dressman Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-{gamma} Cancer Res., October 1, 2005; 65(19): 8869 - 8877. [Abstract] [Full Text] [PDF]

				M. Diverse-Pierluissi G Protein Effectors Sci. Signal., April 26, 2005; 2005(281): tr13 - tr13. [Abstract] [Full Text] [PDF]

				Y. Bai, H. Edamatsu, S. Maeda, H. Saito, N. Suzuki, T. Satoh, and T. Kataoka Crucial Role of Phospholipase C{epsilon} in Chemical Carcinogen-Induced Skin Tumor Development Cancer Res., December 15, 2004; 64(24): 8808 - 8810. [Abstract] [Full Text] [PDF]

				P. T. Ivanova, S. B. Milne, J. S. Forrester, and H. A. Brown LIPID Arrays: New Tools in the Understanding of Membrane Dynamics and Lipid Signaling Mol. Interv., April 1, 2004; 4(2): 86 - 96. [Abstract] [Full Text] [PDF]

This Article Summary Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Related articles in MI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wing, M. R. Articles by Harden, T. K. Search for Related Content PubMed PubMed Citation Articles by Wing, M. R. Articles by Harden, T. K.