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신경세포 시냅스에서 Shank2, Homer 1b와 PLC-β3의 신호전달 복합체 형성
황종익,신금주,류성호,서판길 한국뇌학회 2001 한국뇌학회지 Vol.1 No.2
포스포리파아제 C-베타(phospholipase C-β: PLC-β) 동위효소는 G-proteins-coupled receptors(GPCR)와 그의 신호전달 매개체인 heterotrimeric G proteins에 의해 활성화된다. PLC-β는 효소적 활성에 필요한 영역 외에 카르복시 말단에 PSD-95/Dlg/ZO-1 (PDZ)-binding motif를 가진다. 이 motif는 PLC-β가 PDZ domain을 가진 단백질들과 결합함으로써 GPCR 매개 신호전달에서 특이적인 역할을 수행할 가능성을 제시한다. 이에 본 연구자들은 효모 two-hybrid assay를 통하여 Shank2가 PLC-β3와 결합함을 이전에 확인하였다. 본 연구에서는, 면역침전반응을 통해 두 단백질의 결합은 PLC-β3의 카르복시 말단의 PDZ-binding motif를 통하여 이루어짐을 확인하였고 신경세포의 시냅스에서 mGluR1 및 IP3 수용체와 결합하는 Homer 1b 와 Shank2가 PLC-β3와 함께 위치하는 것을 발견하였다. 이러한 결과는 전자현미경을 이용하여 Homer 1b와 Shank2가 위치하는 PSD 영역에서 PLC-β3가 존재함을 확인하고 mGluR1과 Shank2, Homer 1b, PLC-β3가 해마와 소뇌의 많은 부분에서 동시에 발현되는 것을 확인함으로써 다시 한번 입증되었다. 결과를 종합해 볼 때, 이들 세 단백질은 같은 신경세포의 시냅스에서 발현되어 복합체를 형성함으로써 mGluR1에 의해 매개되는 신호전달을 보다 효율적으로 수행할 수 있을 것으로 예상된다. Phospholipase C-β isotypes activated by G protein-coupled receptors (GPCR) and heterotrimeric G proteins carry a PSD-95/Dlg/ZO-1 (PDZ)-binding motif in their carboxyl terminus. This motif may enable PLC-β isotypes to play specific roles in GPCR signaling through interacting with PDZ-containing proteins. We identified Shank2 as a PLC-β3 binding protein, using yeast two-hybrid system in the previous study, and here we characterized the binding of PLC-β3 with Shank2. Immunoprecipitation study showed that Shank2 interacts with PDZ-binding motif of PLC-β3. Moreover, PLC-β3 was colocalized with Shank2 and Homer 1b that interacts with mGluR1 and IP3 receptor on the synapse of primary-cultured neuronal cells. Immunogold EM also showed that PLC-β3 immunoreactivity was detected at the PSD of the CA1 pyramidal neurons. In several regions of hippocampus and cerebellum, the expression pattern of Shank2 was similar to that of mGluR1, Homer 1b, and PLC-β3. These results suggest that PLC-β3, Shank2, and Homer 1b may act as active intermediates in mGluR1-mediated signal transduction by forming signaling complex in neuronal synapses.
Tumorigenecity of Phosphoinositide-Specific Phospholipase C-??1
Suh, Pann-Ghill 가톨릭 의과학연구원 1998 가톨릭 의과학연구원 국제학술대회 Vol.2 No.-
In conclusion, the increase of GES bindnig proteins and their cooperation might be attributed to the PLC-r1 overexpression, which could transform fibroblast into concerous cells. The transfoming activity of PLC-r1 stems from the SH223 domain of PLC-r1 independently of PLC activity. Therefore. the SH223 domain of PLC-r1 can play a critical role in tumorlgenesis.
Regulation of Phospholipase C-β₃ Signaling by PDZ domain containing proteins
Suh, Pann-Ghill,Ryu, Sung Ho,Hwang, Jong Ik 이화여자대학교 세포신호전달연구센터 2001 고사리 세포신호전달 심포지움 Vol. No.3
Phospholipase C-β isozymes(PLC-β) that mediate G protein-coupled receptor signaling pathway are activated by various extra-cellular signals such as neurotransmitters, hormones, etc. Four isotypes of PLC-β in mammals are differently expressed in various tissues and cell lines. According to some reports, they are selectively activated by the specific ligands. The activation of PLC-β may be determined by distinct factors contributing to specificity in each PLC-β mediated signal transduction. We have identified that carboxyl terminal sequences of PLC-β isozymes harbor putative PDZ-binding motif consisting of different amino acid residues. Many PDZ domain-containing proteins are known to localize at highly specialized sub-membranous regions and to participate in cellular junction formation, receptor or channel clustering and intracellular signaling events. These PDZ-binding motifs of PLC-βs may give the specificity in the signaling pathway by interacting with various PDZ domain-containing proteins. We tried to identify the proteins interacting with C-terminus of PLC-β by using yeast two hybrid system. As a result, Na/H exchanger regulating factor2(NHERF2) from liver cDNA library and Cortactin binding protein I(CortBP1) from brain cDNA library were identified as proteins interacting with PLC-β3. These two molecules interact with PDZ-binding motif of PLC-β3 through their PDZ domain. The Thr and Leu residues in PDZ-binding motif of PLC-β3 are essential to interact with PDZ domain, likely as PDZ domain-mediated interacting mode previously reported. PLC-β3 interacts specifically with NHERF2 or CortBP1, but the other PLC-β isozymes not. When expressed in heterogeneous cells, PLC-β3 and CortBP1 were co-localized in specific subcellular region. In HeLa cells expressing the muscarinic acetylcholine receptor, over-expression of NHERF2 enhanced PLC activity by carbachol stimulation. These studies suggest that NHERF2 and CortBP1 may be the molecular keys to determine the specificity in PLC-β3-mediated signaling pahways, expressing in the different tissues.
The SH3 Domain of Phospholipase C-γ1 Associates with Shc
Suh,Pann-Ghill,Ryu,Sung-Ho,Chang,Jong-Soo,Kim, Myung Jong,Hwang, Jong-Ik The Korea Science and Technology Center 1999 BMB Reports Vol.32 No.2
The SH3 domain of PLC-γ1 has been known to induce DNA synthesis. However, little is known about the putative effector proteins that associate with the domain. In this report, we provide evidence that the SH3 domain of PCL-γ1 associates with Shc, which has been implicated in the activation of p21Ras in response to many growth factors. The association between Shc and PLC-γ1 is enhanced either by ν-Src-induced transformation or EGF-stimulation in vivo and in vitro. Furthermore, from transient expression studies with COS-7 cells, we show that SH3 domain of PLC-γ1 is required for association with Shc in vivo, whereas tyrosyl phosphorylation of PLC-γ1 is not. Taken together, we suggest that Shc might be involved in the PLC-γ1-mediated signaling pathway.
Suh,Pann-Ghill,Ryu,Sung Ho,Kim,Yong,Kim,Su-Jeong,Si,Fu Chun,Kim,Myung Jong The Korea Science and Technology Center 2000 BMB Reports Vol.33 No.2
Phosphoinositide-specific phospholipase C-γ1(PLC-γ1) is a pivotal mediator in the signal transduction cascades induced by many growth factors. Using a yeast two-hybrid system, heat-shock protein 90(Hsp90) was identified as a PLC-γ1-binding protein. A co-immunoprecipitation experiment, using anti-PLC-γ1 antibody, demonstrated an in vivo interaction between Hsp90 and PLC-γ1 in the NIH-3T3 cells. The interaction in NIH-3T3 was unaffected by the PDGF treatment, inducing phosphorylation and activation of PLC-γ1. Direct interaction between Hsp90 and PLC-γ1 was confirmed by in vitro binding experiments using purified Hsp90 and PLC-γ1. Furthermore, Hsp90 increased the PIP₂-hydrolyzing activity of PLC-γ1 up to 2-fold at 0.1μM in vitro. Taken together, we show for the first time, the interaction of PLC-γ1 with Hsp90, both in vivo and in vitro. We suggest that Hsp90 may play a role in PLC-γ1-mediated signal transduction.