Subtype-specific role of phospholipase C-beta in bradykinin and LPA signaling through differential binding of different PDZ scaffold proteins.
Among phospholipase C (PLC) isozymes (beta, gamma, delta, epsilon, zeta and eta), PLC-beta plays a key role in G-protein coupled receptor (GPCR)-mediated signaling. PLC-beta subtypes are often overlapped in their distribution, but have unique knock-out phenotypes in organism, suggesting that each subtype may have the different role even within the same type of cells. In this study, we examined the possibility of the differential coupling of each PLC-beta subtype to GPCRs, and explored the molecular mechanism underlying the specificity. Firstly, we found that PLC-beta1 and PLC-beta 3 are activated by bradykinin (BK) or lysophosphatidic acid (LPA), respectively. BK-triggered phosphoinositides hydrolysis and subsequent Ca(2+) mobilization were abolished specifically by PLC-beta1 silencing, whereas LPA-triggered events were by PLC-beta 3 silencing. Secondly, we showed the evidence that PDZ scaffold proteins is a key mediator for the selective coupling between PLC-beta subtype and GPCR. We found PAR-3 mediates physical interaction between PLC-beta1 and BK receptor, while NHERF2 does between PLC-beta 3 and LPA(2) receptor. Consistently, the silencing of PAR-3 or NHERF2 blunted PLC signaling induced by BK or LPA respectively. Taken together, these data suggest that each subtype of PLC-beta is selectively coupled to GPCR via PDZ scaffold proteins in given cell types and plays differential role in the signaling of various GPCRs.
Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea.
Jung Woong
JW
Choi
Seyoung
S
Lim
Yong-Seok
YS
Oh
Eung-Kyun
EK
Kim
Sun-Hee
SH
Kim
Yun-Hee
YH
Kim
Kyun
K
Heo
Jaeyoon
J
Kim
Jung Kuk
JK
Kim
Yong Ryul
YR
Yang
Sung Ho
SH
Ryu
Pann-Ghill
PG
Suh
D048868:Adaptor Proteins, Signal Transducing; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D054731:PDZ Domains; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D008246:Lysophospholipids; D008565:Membrane Proteins; C509689:PARD3 protein, human; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; C518033:PLCB1 protein, human; C518039:PLCB3 protein, human; D054799:Phospholipase C beta; C032881:lysophosphatidic acid; D001920:Bradykinin; D002118:Calcium