KEGG PATHWAY: ko04072

PATHWAY: ko04072

Entry

ko04072                     Pathway

Name

Phospholipase D signaling pathway

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

ko04072

Phospholipase D signaling pathway

Orthology

K00889

PIP5K; 1-phosphatidylinositol-4-phosphate 5-kinase [EC:2.7.1.68]

K00901

dgkA, DGK; diacylglycerol kinase (ATP) [EC:2.7.1.107]

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01080

PLPP1_2_3; phosphatidate phosphatase [EC:3.1.3.4]

K01115

PLD1_2; phospholipase D1/2 [EC:3.1.4.4]

K01116

PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]

K01313

F2; coagulation factor II (thrombin) [EC:3.4.21.5]

K01528

DNM1_3; dynamin 1/3 [EC:3.6.5.5]

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02677

PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]

K02833

HRAS; GTPase HRas

K03099

SOS; son of sevenless

K03914

F2R, PAR1; coagulation factor II (thrombin) receptor

K04166

AGTR1; angiotensin II receptor type 1

K04175

CXCR1, IL8RA, CD181; C-X-C chemokine receptor type 1

K04226

AVPR1A; arginine vasopressin receptor 1A

K04227

AVPR1B; arginine vasopressin receptor 1B

K04228

AVPR2; arginine vasopressin receptor 2

K04262

PTGFR; prostaglandin F receptor

K04273

LPAR6, P2RY5; lysophosphatidic acid receptor 6

K04275

LPAR4, GPR23; lysophosphatidic acid receptor 4

K04289

LPAR1, EDG2; lysophosphatidic acid receptor 1

K04291

LPAR2, EDG4; lysophosphatidic acid receptor 2

K04294

LPAR3, EDG7; lysophosphatidic acid receptor 3

K04346

GNA12; guanine nucleotide-binding protein subunit alpha-12

K04351

RAPGEF4, EPAC2; Rap guanine nucleotide exchange factor 4

K04357

EGF; epidermal growth factor

K04359

PDGFA; platelet-derived growth factor subunit A

K04361

EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]

K04363

PDGFRA, CD140A; platelet-derived growth factor receptor alpha [EC:2.7.10.1]

K04364

GRB2; growth factor receptor-bound protein 2

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04513

RHOA; Ras homolog gene family, member A

K04526

INS; insulin

K04527

INSR, CD220; insulin receptor [EC:2.7.10.1]

K04603

GRM1; metabotropic glutamate receptor 1

K04604

GRM5; metabotropic glutamate receptor 5

K04605

GRM2; metabotropic glutamate receptor 2

K04606

GRM3; metabotropic glutamate receptor 3

K04607

GRM4; metabotropic glutamate receptor 4

K04608

GRM6; metabotropic glutamate receptor 6

K04609

GRM7; metabotropic glutamate receptor 7

K04610

GRM8; metabotropic glutamate receptor 8

K04632

GNAS; guanine nucleotide-binding protein G(s) subunit alpha

K04639

GNA13; guanine nucleotide-binding protein subunit alpha-13

K04718

SPHK; sphingosine kinase [EC:2.7.1.91]

K05050

CXCR2, IL8RB, CD182; C-X-C chemokine receptor type 2

K05089

PDGFRB, CD140B; platelet-derived growth factor receptor beta [EC:2.7.10.1]

K05091

KIT, SCFR, CD117; proto-oncogene tyrosine-protein kinase Kit [EC:2.7.10.1]

K05242

AVP; arginine vasopressin

K05450

PDGFC_D; platelet derived growth factor C/D

K05461

KITLG; KIT ligand

K05703

FYN; tyrosine-protein kinase Fyn [EC:2.7.10.2]

K05855

SYK; spleen tyrosine kinase [EC:2.7.10.2]

K05858

PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]

K05859

PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]

K05871

PTK2B, FAK2; focal adhesion kinase 2 [EC:2.7.10.2]

K06279

SHC1; SHC-transforming protein 1

K06856

IGH; immunoglobulin heavy chain

K07203

MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]

K07206

TSC1; tuberous sclerosis 1

K07207

TSC2; tuberous sclerosis 2

K07208

RHEB; Ras homolog enriched in brain

K07293

PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48]

K07827

KRAS, KRAS2; GTPase KRas

K07828

NRAS; GTPase NRas

K07829

RRAS; Ras-related protein R-Ras

K07830

RRAS2, TC21; Ras-related protein R-Ras2

K07831

MRAS; Ras-related protein M-Ras

K07834

RALA; Ras-related protein Ral-A

K07835

RALB; Ras-related protein Ral-B

K07937

ARF1_2; ADP-ribosylation factor 1/2

K07941

ARF6; ADP-ribosylation factor 6

K07983

FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma

K08014

RAPGEF3, EPAC1; Rap guanine nucleotide exchange factor 3

K08041

ADCY1; adenylate cyclase 1 [EC:4.6.1.1]

K08042

ADCY2; adenylate cyclase 2 [EC:4.6.1.1]

K08043

ADCY3; adenylate cyclase 3 [EC:4.6.1.1]

K08044

ADCY4; adenylate cyclase 4 [EC:4.6.1.1]

K08045

ADCY5; adenylate cyclase 5 [EC:4.6.1.1]

K08046

ADCY6; adenylate cyclase 6 [EC:4.6.1.1]

K08047

ADCY7; adenylate cyclase 7 [EC:4.6.1.1]

K08048

ADCY8; adenylate cyclase 8 [EC:4.6.1.1]

K08049

ADCY9; adenylate cyclase 9 [EC:4.6.1.1]

K08089

FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha

K08090

MS4A2, FCER1B; high affinity immunoglobulin epsilon receptor subunit beta

K08091

GAB2; GRB2-associated-binding protein 2

K08390

LPAR5, GPR92; lysophosphatidic acid receptor 5

K08732

RALGDS; ral guanine nucleotide dissociation stimulator

K09593

GAB1; GRB2-associated-binding protein 1

K09821

AGT, SERPINA8; angiotensinogen

K10030

IL8, CXCL8; interleukin 8

K13509

AGPAT1_2; lysophosphatidate acyltransferase [EC:2.3.1.51]

K13523

AGPAT3_4; lysophosphatidic acid acyltransferase / lysophosphatidylinositol acyltransferase [EC:2.3.1.51 2.3.1.-]

K16342

PLA2G4, CPLA2; cytosolic phospholipase A2 [EC:3.1.1.4]

K17386

PDGFB; platelet-derived growth factor subunit B

K17447

SHC2; SHC-transforming protein 2

K17448

SHC3; SHC-transforming protein 3

K17449

SHC4; SHC-transforming protein 4

K18441

CYTH; cytohesin

K19007

AGPAT5; lysophosphatidiate acyltransferase [EC:2.3.1.51]

K21289

PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:2.7.1.153]

K21290

PIK3R5_6; phosphoinositide-3-kinase regulatory subunit 5/6

K23484

DNM2; dynamin 2

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