KEGG   PATHWAY: ko04072Help
ko04072                     Pathway                                

Phospholipase D signaling pathway
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.
Environmental Information Processing; Signal transduction
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ko04072  Phospholipase D signaling pathway

Ortholog table
K04357  epidermal growth factor
K04359  platelet-derived growth factor subunit A
K17386  platelet-derived growth factor subunit B
K05450  platelet derived growth factor C/D
K05461  KIT ligand
K04526  insulin
K04361  epidermal growth factor receptor [EC:]
K04363  platelet-derived growth factor receptor alpha [EC:]
K05089  platelet-derived growth factor receptor beta [EC:]
K05091  proto-oncogene tyrosine-protein kinase Kit [EC:]
K04527  insulin receptor [EC:]
K04364  growth factor receptor-binding protein 2
K09593  GRB2-associated-binding protein 1
K08091  growth factor receptor bound protein 2-associated protein 2
K06279  SHC-transforming protein 1
K17447  SHC-transforming protein 2
K17448  SHC-transforming protein 3
K17449  SHC-transforming protein 4
K07293  tyrosine-protein phosphatase non-receptor type 11 [EC:]
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K07831  Ras-related protein M-Ras
K07829  Ras-related protein R-Ras
K07830  Ras-related protein R-Ras2
K08732  ral guanine nucleotide dissociation stimulator
K07834  Ras-related protein Ral-A
K07835  Ras-related protein Ral-B
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K07206  tuberous sclerosis 1
K07207  tuberous sclerosis 2
K07208  Ras homolog enriched in brain
K07203  serine/threonine-protein kinase mTOR [EC:]
K04513  Ras homolog gene family, member A
K07937  ADP-ribosylation factor 1
K07941  ADP-ribosylation factor 6
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K06856  immunoglobulin heavy chain
K08089  high affinity immunoglobulin epsilon receptor subunit alpha
K08090  high affinity immunoglobulin epsilon receptor subunit beta
K07983  high affinity immunoglobulin epsilon receptor subunit gamma
K05703  tyrosine-protein kinase Fyn [EC:]
K05855  spleen tyrosine kinase [EC:]
K02677  classical protein kinase C alpha type [EC:]
K01115  phospholipase D1/2 [EC:]
K16342  cytosolic phospholipase A2 [EC:]
K13509  lysophosphatidate acyltransferase [EC:]
K13523  lysophosphatidic acid acyltransferase / lysophosphatidylinositol acyltransferase [EC:2.3.1.-]
K19007  lysophosphatidiate acyltransferase [EC:]
K04718  sphingosine kinase [EC:]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K00889  1-phosphatidylinositol-4-phosphate 5-kinase [EC:]
K00901  diacylglycerol kinase (ATP) [EC:]
K01080  phosphatidate phosphatase [EC:]
K05242  arginine vasopressin
K10030  interleukin 8
K04166  angiotensin II receptor type 1
K03914  coagulation factor II (thrombin) receptor
K04603  metabotropic glutamate receptor 1
K04605  metabotropic glutamate receptor 2/3
K04607  metabotropic glutamate receptor 4
K04604  metabotropic glutamate receptor 5
K04608  metabotropic glutamate receptor 6/7/8
K04226  arginine vasopressin receptor 1A
K04227  arginine vasopressin receptor 1B
K04228  arginine vasopressin receptor 2
K04289  lysophosphatidic acid receptor 1
K04291  lysophosphatidic acid receptor 2
K04294  lysophosphatidic acid receptor 3
K04275  lysophosphatidic acid receptor 4
K08390  lysophosphatidic acid receptor 5
K04273  lysophosphatidic acid receptor 6
K04262  prostaglandin F receptor
K04175  C-X-C chemokine receptor type 1
K05050  C-X-C chemokine receptor type 2
K05858  phosphatidylinositol phospholipase C, beta [EC:]
K04346  guanine nucleotide-binding protein subunit alpha-12
K05871  focal adhesion kinase 2 [EC:]
K04639  guanine nucleotide-binding protein subunit alpha-13
K21289  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:]
K21290  phosphoinositide-3-kinase regulatory subunit 5/6
K18441  cytohesin
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K08041  adenylate cyclase 1 [EC:]
K08042  adenylate cyclase 2 [EC:]
K08043  adenylate cyclase 3 [EC:]
K08044  adenylate cyclase 4 [EC:]
K08045  adenylate cyclase 5 [EC:]
K08046  adenylate cyclase 6 [EC:]
K08047  adenylate cyclase 7 [EC:]
K08048  adenylate cyclase 8 [EC:]
K08049  adenylate cyclase 9 [EC:]
K08014  Rap guanine nucleotide exchange factor 3
K04351  Rap guanine nucleotide exchange factor 4
K01528  dynamin GTPase [EC:]
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
C00752  Thrombin
C01245  D-myo-Inositol 1,4,5-trisphosphate
C02135  Angiotensin II
C04637  1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06124  Sphingosine 1-phosphate
Oude Weernink PA, Lopez de Jesus M, Schmidt M
Phospholipase D signaling: orchestration by PIP2 and small GTPases.
Naunyn Schmiedebergs Arch Pharmacol 374:399-411 (2007)
Selvy PE, Lavieri RR, Lindsley CW, Brown HA
Phospholipase D: enzymology, functionality, and chemical modulation.
Chem Rev 111:6064-119 (2011)
Brandenburg LO, Pufe T, Koch T
Role of phospholipase d in g-protein coupled receptor function.
Membranes (Basel) 4:302-18 (2014)
Oude Weernink PA, Han L, Jakobs KH, Schmidt M
Dynamic phospholipid signaling by G protein-coupled receptors.
Biochim Biophys Acta 1768:888-900 (2007)
Foster DA, Salloum D, Menon D, Frias MA
Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).
J Biol Chem 289:22583-8 (2014)
Jenkins GM, Frohman MA
Phospholipase D: a lipid centric review.
Cell Mol Life Sci 62:2305-16 (2005)
Metcalfe DD, Peavy RD, Gilfillan AM
Mechanisms of mast cell signaling in anaphylaxis.
J Allergy Clin Immunol 124:639-46; quiz 647-8 (2009)
Kalesnikoff J, Galli SJ
New developments in mast cell biology.
Nat Immunol 9:1215-23 (2008)
Cockcroft S, Way G, O'Luanaigh N, Pardo R, Sarri E, Fensome A
Signalling role for ARF and phospholipase D in mast cell exocytosis stimulated by crosslinking of the high affinity FcepsilonR1 receptor.
Mol Immunol 38:1277-82 (2002)
Lee CS, Kim KL, Jang JH, Choi YS, Suh PG, Ryu SH
The roles of phospholipase D in EGFR signaling.
Biochim Biophys Acta 1791:862-8 (2009)
Lee CS, Kim IS, Park JB, Lee MN, Lee HY, Suh PG, Ryu SH
The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis.
Nat Cell Biol 8:477-84 (2006)
Kam Y, Exton JH
Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid.
FASEB J 18:311-9 (2004)
Kozawa O, Blume-Jensen P, Heldin CH, Ronnstrand L
Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release.
Eur J Biochem 248:149-55 (1997)
Slaaby R, Du G, Altshuller YM, Frohman MA, Seedorf K
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.
Biochem J 351 Pt 3:613-9 (2000)
Fahimi-Vahid M, Gosau N, Michalek C, Han L, Jakobs KH, Schmidt M, Roberts N, Avkiran M, Wieland T
Distinct signaling pathways mediate cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin.
J Mol Cell Cardiol 34:441-53 (2002)
Freeman EJ
The Ang II-induced growth of vascular smooth muscle cells involves a phospholipase D-mediated signaling mechanism.
Arch Biochem Biophys 374:363-70 (2000)
Naro F, Donchenko V, Minotti S, Zolla L, Molinaro M, Adamo S
Role of phospholipase C and D signalling pathways in vasopressin-dependent myogenic differentiation.
Murdoch C, Finn A
Chemokine receptors and their role in inflammation and infectious diseases.
Blood 95:3032-43 (2000)
Sugiyama T, Sakai T, Nozawa Y, Oka N
Prostaglandin F2 alpha-stimulated phospholipase D activation in osteoblast-like MC3T3-E1 cells: involvement in sustained 1,2-diacylglycerol production.
Biochem J 298 ( Pt 2):479-84 (1994)
Foster DA
Regulation of mTOR by phosphatidic acid?
Cancer Res 67:1-4 (2007)
Delon C, Manifava M, Wood E, Thompson D, Krugmann S, Pyne S, Ktistakis NT
Sphingosine kinase 1 is an intracellular effector of phosphatidic acid.
J Biol Chem 279:44763-74 (2004)
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
Phospholipase signalling networks in cancer.
Nat Rev Cancer 12:782-92 (2012)
Foster DA
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
Biochim Biophys Acta 1791:949-55 (2009)
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