| Structural highlights
Disease
PLCE1_HUMAN Familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis;Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis. The disease is caused by mutations affecting the gene represented in this entry.
Function
PLCE1_HUMAN The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. PLCE1 is a bifunctional enzyme which also regulates small GTPases of the Ras superfamily through its Ras guanine-exchange factor (RasGEF) activity. As an effector of heterotrimeric and small G-protein, it may play a role in cell survival, cell growth, actin organization and T-cell activation.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Ras proteins signal to a number of distinct pathways by interacting with diverse effectors. Studies of ras/effector interactions have focused on three classes, Raf kinases, ral guanylnucleotide-exchange factors, and phosphatidylinositol-3-kinases. Here we describe ras interactions with another effector, the recently identified phospholipase C epsilon (PLCepsilon). We solved structures of PLCepsilon RA domains (RA1 and RA2) by NMR and the structure of the RA2/ras complex by X-ray crystallography. Although the similarity between ubiquitin-like folds of RA1 and RA2 proves that they are homologs, only RA2 can bind ras. Some of the features of the RA2/ras interface are unique to PLCepsilon, while the ability to make contacts with both switch I and II regions of ras is shared only with phosphatidylinositol-3-kinase. Studies of PLCepsilon regulation suggest that, in a cellular context, the RA2 domain, in a mode specific to PLCepsilon, has a role in membrane targeting with further regulatory impact on PLC activity.
Structural and mechanistic insights into ras association domains of phospholipase C epsilon.,Bunney TD, Harris R, Gandarillas NL, Josephs MB, Roe SM, Sorli SC, Paterson HF, Rodrigues-Lima F, Esposito D, Ponting CP, Gierschik P, Pearl LH, Driscoll PC, Katan M Mol Cell. 2006 Feb 17;21(4):495-507. PMID:16483931[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW. A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway. J Biol Chem. 2001 Jan 26;276(4):2758-65. Epub 2000 Oct 5. PMID:11022047 doi:http://dx.doi.org/10.1074/jbc.M008119200
- ↑ Jin TG, Satoh T, Liao Y, Song C, Gao X, Kariya K, Hu CD, Kataoka T. Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling. J Biol Chem. 2001 Aug 10;276(32):30301-7. Epub 2001 Jun 6. PMID:11395506 doi:http://dx.doi.org/10.1074/jbc.M103530200
- ↑ Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH. A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol. 2001 Nov;3(11):1020-4. PMID:11715024 doi:http://dx.doi.org/10.1038/ncb1101-1020
- ↑ Evellin S, Nolte J, Tysack K, vom Dorp F, Thiel M, Weernink PA, Jakobs KH, Webb EJ, Lomasney JW, Schmidt M. Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B. J Biol Chem. 2002 May 10;277(19):16805-13. Epub 2002 Mar 4. PMID:11877431 doi:http://dx.doi.org/10.1074/jbc.M112024200
- ↑ Czyzyk J, Brogdon JL, Badou A, Henegariu O, Preston Hurlburt P, Flavell R, Bottomly K. Activation of CD4 T cells by Raf-independent effectors of Ras. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6003-8. Epub 2003 Apr 29. PMID:12721365 doi:http://dx.doi.org/10.1073/pnas.1031494100
- ↑ Ada-Nguema AS, Xenias H, Hofman JM, Wiggins CH, Sheetz MP, Keely PJ. The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon. J Cell Sci. 2006 Apr 1;119(Pt 7):1307-19. Epub 2006 Mar 14. PMID:16537651 doi:http://dx.doi.org/10.1242/jcs.02835
- ↑ Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O'toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006 Dec;38(12):1397-405. Epub 2006 Nov 5. PMID:17086182 doi:http://dx.doi.org/ng1918
- ↑ Bunney TD, Harris R, Gandarillas NL, Josephs MB, Roe SM, Sorli SC, Paterson HF, Rodrigues-Lima F, Esposito D, Ponting CP, Gierschik P, Pearl LH, Driscoll PC, Katan M. Structural and mechanistic insights into ras association domains of phospholipase C epsilon. Mol Cell. 2006 Feb 17;21(4):495-507. PMID:16483931 doi:http://dx.doi.org/10.1016/j.molcel.2006.01.008
|
