KEGG   PATHWAY: rno04072
Entry
rno04072                    Pathway                                
Name
Phospholipase D signaling pathway - Rattus norvegicus (rat)
Description
Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2). The PLD-produced PA activates signaling proteins and acts as a node within the membrane to which signaling proteins translocate. Several signaling proteins, including Raf-1 and mTOR, directly bind PA to mediate translocation or activation, respectively.
Class
Environmental Information Processing; Signal transduction
Pathway map
rno04072  Phospholipase D signaling pathway
rno04072

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
25313  Egf; pro-epidermal growth factor precursor [KO:K04357]
25266  Pdgfa; platelet-derived growth factor subunit A precursor [KO:K04359]
24628  Pdgfb; platelet-derived growth factor subunit B precursor [KO:K17386]
79429  Pdgfc; platelet-derived growth factor C precursor [KO:K05450]
66018  Pdgfd; platelet-derived growth factor D precursor [KO:K05450]
60427  Kitlg; kit ligand isoform 1 precursor [KO:K05461]
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24329  Egfr; epidermal growth factor receptor isoform 2 precursor [KO:K04361] [EC:2.7.10.1]
25267  Pdgfra; platelet-derived growth factor receptor alpha precursor [KO:K04363] [EC:2.7.10.1]
24629  Pdgfrb; platelet-derived growth factor receptor beta precursor [KO:K05089] [EC:2.7.10.1]
64030  Kit; mast/stem cell growth factor receptor Kit precursor [KO:K05091] [EC:2.7.10.1]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:2.7.10.1]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
361388  Gab1; GRB2-associated-binding protein 1 [KO:K09593]
84477  Gab2; GRB2-associated-binding protein 2 [KO:K08091]
85385  Shc1; SHC-transforming protein 1 isoform b [KO:K06279]
314612  Shc2; SHC-transforming protein 2 [KO:K17447]
114858  Shc3; SHC-transforming protein 3 [KO:K17448]
679845  Shc4; SHC-transforming protein 4 [KO:K17449]
25622  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform 2 [KO:K07293] [EC:3.1.3.48]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
25482  Mras; ras-related protein M-Ras [KO:K07831]
361568  Rras; ras-related protein R-Ras [KO:K07829]
365355  Rras2; ras-related protein R-Ras2 [KO:K07830]
29622  Ralgds; ral guanine nucleotide dissociation stimulator isoform 1 [KO:K08732]
81757  Rala; ras-related protein Ral-A [KO:K07834]
116546  Ralb; ras-related protein Ral-B [KO:K07835]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
60445  Tsc1; hamartin [KO:K07206]
24855  Tsc2; tuberin [KO:K07207]
26954  Rheb; GTP-binding protein Rheb [KO:K07208]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
117273  Rhoa; transforming protein RhoA [KO:K04513]
297173  RSA-14-44; ras homolog gene family, member A [KO:K04513]
64310  Arf1; ADP-ribosylation factor 1 [KO:K07937]
79119  Arf2; ADP-ribosylation factor 2 [KO:K07937]
79121  Arf6; ADP-ribosylation factor 6 [KO:K07941]
25738  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
29337  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
25047  Fcer1a; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
25316  Ms4a2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
25441  Fcer1g; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
25150  Fyn; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
25155  Syk; tyrosine-protein kinase SYK [KO:K05855] [EC:2.7.10.2]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25097  Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
25096  Pld1; phospholipase D1 isoform 2 [KO:K01115] [EC:3.1.4.4]
296091  Pla2g4e; cytosolic phospholipase A2 epsilon isoform X1 [KO:K16342] [EC:3.1.1.4]
24653  Pla2g4a; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
311341  Pla2g4b; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
691905  Pla2g4d; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
691907  Pla2g4f; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
691810  Pla2g4c; cytosolic phospholipase A2 gamma [KO:K16342] [EC:3.1.1.4]
406165  Agpat1; 1-acyl-sn-glycerol-3-phosphate acyltransferase alpha [KO:K13509] [EC:2.3.1.51]
311821  Agpat2; 1-acyl-sn-glycerol-3-phosphate acyltransferase beta precursor [KO:K13509] [EC:2.3.1.51]
294324  Agpat3; 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma [KO:K13523] [EC:2.3.1.51 2.3.1.-]
170919  Agpat4; 1-acyl-sn-glycerol-3-phosphate acyltransferase delta [KO:K13523] [EC:2.3.1.51 2.3.1.-]
306582  Agpat5; 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon isoform 1 [KO:K19007] [EC:2.3.1.51]
308589  Sphk2; sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
170897  Sphk1; sphingosine kinase 1 isoform b [KO:K04718] [EC:2.7.1.91]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
309419  Pip5k1b; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:2.7.1.68]
314641  Pip5k1c; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform c [KO:K00889] [EC:2.7.1.68]
365865  Pip5k1a; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha [KO:K00889] [EC:2.7.1.68]
81821  Dgkz; diacylglycerol kinase zeta isoform 2 [KO:K00901] [EC:2.7.1.107]
25666  Dgkg; diacylglycerol kinase gamma [KO:K00901] [EC:2.7.1.107]
54248  Dgkb; diacylglycerol kinase beta [KO:K00901] [EC:2.7.1.107]
140866  Dgka; diacylglycerol kinase alpha [KO:K00901] [EC:2.7.1.107]
688705  Dgki; diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
361076  Dgkh; diacylglycerol kinase eta isoform X4 [KO:K00901] [EC:2.7.1.107]
368088  Dgkd; diacylglycerol kinase delta isoform X2 [KO:K00901] [EC:2.7.1.107]
100361138  Dgkq; diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
367745  Dgkk; diacylglycerol kinase kappa isoform X1 [KO:K00901] [EC:2.7.1.107]
64369  Plpp1; phospholipid phosphatase 1 [KO:K01080] [EC:3.1.3.4]
246115  Plpp2; phospholipid phosphatase 2 [KO:K01080] [EC:3.1.3.4]
192270  Plpp3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
29251  F2; prothrombin precursor [KO:K01313] [EC:3.4.21.5]
24179  Agt; angiotensinogen precursor [KO:K09821]
24221  Avp; vasopressin-neurophysin 2-copeptin preproprotein [KO:K05242]
24180  Agtr1a; type-1 angiotensin II receptor A [KO:K04166]
81638  Agtr1b; type-1 angiotensin II receptor B [KO:K04166]
25439  F2r; proteinase-activated receptor 1 precursor [KO:K03914]
24414  Grm1; metabotropic glutamate receptor 1 isoform alpha precursor [KO:K04603]
24415  Grm2; metabotropic glutamate receptor 2 precursor [KO:K04605]
24416  Grm3; metabotropic glutamate receptor 3 precursor [KO:K04606]
24417  Grm4; metabotropic glutamate receptor 4 precursor [KO:K04607]
24418  Grm5; metabotropic glutamate receptor 5 precursor [KO:K04604]
24419  Grm6; metabotropic glutamate receptor 6 precursor [KO:K04608]
81672  Grm7; metabotropic glutamate receptor 7 precursor [KO:K04609]
60590  Grm8; metabotropic glutamate receptor 8 precursor [KO:K04610]
25107  Avpr1a; vasopressin V1a receptor [KO:K04226]
100909648  Avpr1b; vasopressin V1b receptor [KO:K04227]
25108  Avpr2; vasopressin V2 receptor [KO:K04228]
116744  Lpar1; lysophosphatidic acid receptor 1 [KO:K04289]
66025  Lpar3; lysophosphatidic acid receptor 3 [KO:K04294]
302378  Lpar4; lysophosphatidic acid receptor 4 [KO:K04275]
500317  Lpar5; lysophosphatidic acid receptor 5 [KO:K08390]
691774  Lpar6; lysophosphatidic acid receptor 6 [KO:K04273]
25652  Ptgfr; prostaglandin F2-alpha receptor [KO:K04262]
54258  Cxcr1; C-X-C chemokine receptor type 1 [KO:K04175]
29385  Cxcr2; C-X-C chemokine receptor type 2 [KO:K05050]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
81663  Gna12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
50646  Ptk2b; protein-tyrosine kinase 2-beta [KO:K05871] [EC:2.7.10.2]
303634  Gna13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
298947  Pik3cg; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
497931  Pik3r5; phosphoinositide 3-kinase regulatory subunit 5 [KO:K21290]
497932  Pik3r6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
116691  Cyth1; cytohesin-1 [KO:K18441]
116692  Cyth2; cytohesin-2 isoform 1 [KO:K18441]
116693  Cyth3; cytohesin-3 [KO:K18441]
500906  Cyth4; cytohesin-4 isoform 2 [KO:K18441]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
59326  Rapgef3; rap guanine nucleotide exchange factor 3 [KO:K08014]
252857  Rapgef4; rap guanine nucleotide exchange factor 4 [KO:K04351]
140694  Dnm1; dynamin-1 [KO:K01528] [EC:3.6.5.5]
171574  Dnm3; dynamin-3 [KO:K01528] [EC:3.6.5.5]
25751  Dnm2; dynamin-2 [KO:K23484] [EC:3.6.5.5]
Compound
C00025  L-Glutamate
C00076  Calcium cation
C00165  Diacylglycerol
C00416  Phosphatidate
C00575  3',5'-Cyclic AMP
C00639  Prostaglandin F2alpha
C00681  1-Acyl-sn-glycerol 3-phosphate
C01245  D-myo-Inositol 1,4,5-trisphosphate
C04637  1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06124  Sphingosine 1-phosphate
Reference
PMID:17245604
  Authors
Oude Weernink PA, Lopez de Jesus M, Schmidt M
  Title
Phospholipase D signaling: orchestration by PIP2 and small GTPases.
  Journal
Naunyn Schmiedebergs Arch Pharmacol 374:399-411 (2007)
DOI:10.1007/s00210-007-0131-4
Reference
PMID:21936578
  Authors
Selvy PE, Lavieri RR, Lindsley CW, Brown HA
  Title
Phospholipase D: enzymology, functionality, and chemical modulation.
  Journal
Chem Rev 111:6064-119 (2011)
DOI:10.1021/cr200296t
Reference
PMID:24995811
  Authors
Brandenburg LO, Pufe T, Koch T
  Title
Role of phospholipase d in g-protein coupled receptor function.
  Journal
Membranes (Basel) 4:302-18 (2014)
DOI:10.3390/membranes4030302
Reference
PMID:17054901
  Authors
Oude Weernink PA, Han L, Jakobs KH, Schmidt M
  Title
Dynamic phospholipid signaling by G protein-coupled receptors.
  Journal
Biochim Biophys Acta 1768:888-900 (2007)
DOI:10.1016/j.bbamem.2006.09.012
Reference
PMID:24990952
  Authors
Foster DA, Salloum D, Menon D, Frias MA
  Title
Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).
  Journal
J Biol Chem 289:22583-8 (2014)
DOI:10.1074/jbc.R114.566091
Reference
PMID:16143829
  Authors
Jenkins GM, Frohman MA
  Title
Phospholipase D: a lipid centric review.
  Journal
Cell Mol Life Sci 62:2305-16 (2005)
DOI:10.1007/s00018-005-5195-z
Reference
PMID:19815110
  Authors
Metcalfe DD, Peavy RD, Gilfillan AM
  Title
Mechanisms of mast cell signaling in anaphylaxis.
  Journal
J Allergy Clin Immunol 124:639-46; quiz 647-8 (2009)
DOI:10.1016/j.jaci.2009.08.035
Reference
PMID:18936782
  Authors
Kalesnikoff J, Galli SJ
  Title
New developments in mast cell biology.
  Journal
Nat Immunol 9:1215-23 (2008)
DOI:10.1038/ni.f.216
Reference
PMID:12217395
  Authors
Cockcroft S, Way G, O'Luanaigh N, Pardo R, Sarri E, Fensome A
  Title
Signalling role for ARF and phospholipase D in mast cell exocytosis stimulated by crosslinking of the high affinity FcepsilonR1 receptor.
  Journal
Mol Immunol 38:1277-82 (2002)
DOI:10.1016/S0161-5890(02)00075-5
Reference
PMID:19410013
  Authors
Lee CS, Kim KL, Jang JH, Choi YS, Suh PG, Ryu SH
  Title
The roles of phospholipase D in EGFR signaling.
  Journal
Biochim Biophys Acta 1791:862-8 (2009)
DOI:10.1016/j.bbalip.2009.04.007
Reference
PMID:16622417
  Authors
Lee CS, Kim IS, Park JB, Lee MN, Lee HY, Suh PG, Ryu SH
  Title
The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis.
  Journal
Nat Cell Biol 8:477-84 (2006)
DOI:10.1038/ncb1401
Reference
PMID:14769825
  Authors
Kam Y, Exton JH
  Title
Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid.
  Journal
FASEB J 18:311-9 (2004)
DOI:10.1096/fj.03-0731com
Reference
PMID:9310372
  Authors
Kozawa O, Blume-Jensen P, Heldin CH, Ronnstrand L
  Title
Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release.
  Journal
Eur J Biochem 248:149-55 (1997)
DOI:10.1111/j.1432-1033.1997.00149.x
Reference
PMID:11042115
  Authors
Slaaby R, Du G, Altshuller YM, Frohman MA, Seedorf K
  Title
Insulin-induced phospholipase D1 and phospholipase D2 activity in human embryonic kidney-293 cells mediated by the phospholipase C gamma and protein kinase C alpha signalling cascade.
  Journal
Biochem J 351 Pt 3:613-9 (2000)
DOI:10.1042/bj3510613
Reference
PMID:11991733
  Authors
Fahimi-Vahid M, Gosau N, Michalek C, Han L, Jakobs KH, Schmidt M, Roberts N, Avkiran M, Wieland T
  Title
Distinct signaling pathways mediate cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin.
  Journal
J Mol Cell Cardiol 34:441-53 (2002)
DOI:10.1006/jmcc.2002.1525
Reference
PMID:10666319
  Authors
Freeman EJ
  Title
The Ang II-induced growth of vascular smooth muscle cells involves a phospholipase D-mediated signaling mechanism.
  Journal
Arch Biochem Biophys 374:363-70 (2000)
DOI:10.1006/abbi.1999.1608
Reference
PMID:9119890
  Authors
Naro F, Donchenko V, Minotti S, Zolla L, Molinaro M, Adamo S
  Title
Role of phospholipase C and D signalling pathways in vasopressin-dependent myogenic differentiation.
  Journal
J Cell Physiol 171:34-42 (1997)
DOI:10.1002/(SICI)1097-4652(199704)171:1<34::AID-JCP5>3.0.CO;2-I
Reference
PMID:10807766
  Authors
Murdoch C, Finn A
  Title
Chemokine receptors and their role in inflammation and infectious diseases.
  Journal
Blood 95:3032-43 (2000)
Reference
PMID:8135758
  Authors
Sugiyama T, Sakai T, Nozawa Y, Oka N
  Title
Prostaglandin F2 alpha-stimulated phospholipase D activation in osteoblast-like MC3T3-E1 cells: involvement in sustained 1,2-diacylglycerol production.
  Journal
Biochem J 298 ( Pt 2):479-84 (1994)
DOI:10.1042/bj2980479
Reference
PMID:17210675
  Authors
Foster DA
  Title
Regulation of mTOR by phosphatidic acid?
  Journal
Cancer Res 67:1-4 (2007)
DOI:10.1158/0008-5472.CAN-06-3016
Reference
PMID:15310762
  Authors
Delon C, Manifava M, Wood E, Thompson D, Krugmann S, Pyne S, Ktistakis NT
  Title
Sphingosine kinase 1 is an intracellular effector of phosphatidic acid.
  Journal
J Biol Chem 279:44763-74 (2004)
DOI:10.1074/jbc.M405771200
Reference
PMID:23076158
  Authors
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
  Title
Phospholipase signalling networks in cancer.
  Journal
Nat Rev Cancer 12:782-92 (2012)
DOI:10.1038/nrc3379
Reference
PMID:19264150
  Authors
Foster DA
  Title
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
  Journal
Biochim Biophys Acta 1791:949-55 (2009)
DOI:10.1016/j.bbalip.2009.02.009
Related
pathway
rno00561  Glycerolipid metabolism
rno04010  MAPK signaling pathway
rno04014  Ras signaling pathway
rno04020  Calcium signaling pathway
rno04024  cAMP signaling pathway
rno04071  Sphingolipid signaling pathway
rno04144  Endocytosis
rno04150  mTOR signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04664  Fc epsilon RI signaling pathway
KO pathway
ko04072   
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