[논문]Phospholipase Cγ의 생리적 기능과 질병과 연관된 돌연변이

장현준; 최장현; 장종수

doi:10.5352/jls.2020.30.9.826

Phospholipase Cγ의 생리적 기능과 질병과 연관된 돌연변이
Physiological Roles of Phospholipase Cγ and Its Mutations in Human Disease 원문보기

생명과학회지 = Journal of life science, v.30 no.9, 2020년, pp.826 - 833

장현준 (울산과학기술원 생명과학부) , 최장현 (울산과학기술원 생명과학부) , 장종수 (대진대학교 생명화학부)

초록
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Phospholipase C gamma (PLCγ)는 phosphatidylinositol을 가수분해하여 신호전달 과정에 참여하는 PLC의 주요한 isotype으로 γ-specific array의 특징적인 구조를 바탕으로 receptor tyrosine kinases 및 non-receptor tyrosine kinase 신호를 주로 매개한다. PLCγ1과 PLCγ2의 두 isozyme이 존재하며 다양한 세포에서 발현하여 cell proliferation, migration 및 differentiation 등 여러 세포작용을 조절하고 있다. 최근의 연구들에서 PLCγ 돌연변이가 cancer와 immune disease 및 brain disorder 등에 연관된다는 것이 밝혀지고 있으며 genetic model을 통해 PLCγ의 생리적·병리적 기능이 제시되었다. 본 리뷰에서는 최신의 연구 결과들을 바탕으로 PLCγ의 구조와 활성 조절 기전에 대해 기술하고 나아가 여러 질병의 발병과 진행에서 보고된 PLCγ의 돌연변이와 knockout 마우스를 활용한 연구 결과를 바탕으로 생리적·병리적 관점에서 PLCγ의 역할에 대해 고찰하였다.

Abstract ▼ AI-Helper

Phospholipase C gamma (PLCγ) has critical roles in receptor tyrosine kinase- and non-receptor tyrosine kinase-mediated cellular signaling relating to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to produce inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG), which promote protein kinase C (PKC) and Ca2+ signaling to their downstream cellular targets. PLCγ has two isozymes called PLCγ1 and PLCγ2, which control cell growth and differentiation. In addition to catalytically active X- and Y-domains, both isotypes contain two Src homology 2 (SH2) domains and an SH3 domain for protein-protein interaction when the cells are activated by ligand stimulation. PLCγ also contains two pleckstrin homology (PH) domains for membrane-associated phosphoinositide binding and protein-protein interactions. While PLCγ1 is widely expressed and appears to regulate intracellular signaling in many tissues, PLCγ2 expression is restricted to cells of hematopoietic systems and seems to play a role in the regulation of immune response. A distinct mechanism for PLCγ activation is linked to an increase in phosphorylation of specific tyrosine residue, Y783. Recent studies have demonstrated that PLCγ mutations are closely related to cancer, immune disease, and brain disorders. Our review focused on the physiological roles of PLCγ by means of its structure and enzyme activity and the pathological functions of PLCγ via mutational analysis obtained from various human diseases and PLCγ knockout mice.

주제어

표/그림 (2)

그림 Fig. 1. PLCγ structure. (A) PLCγ has PLC-core (PH, EF-hand, TIM (X-Y domain), C2 domain) and characteristic γ-specific arrays (spPH, nSH2, cSH2, SH3, spPH). (B) PLCγ crystal structure. Image from the RCSB PDB (rcsb.org) of PDB ID: 6PBC [3, 16].
그림 Fig. 2. Schematic diagram of activation of PLCγ1. In autoinhibition state, γ-specific arrays (γSA) covers the PLCγ1 active site and blocks contact with the substrate of plasma membrane. When nSH2 domain recognized and bound the phosphorylation site of activated receptor tyrosine kinases (RTK) (for example, pY766 of FGFR1), the kinase domain of RTK weakens the binding of cSH2 domain to C2 domain of PLC-core and phosphorylates Y783. Phosphorylated Y783 binds to the cSH2 domain and separates the cSH2 domain from the C2 domain, allowing the active site to access the membrane, thereby activating PLCγ1.

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문제 정의

본 리뷰에서는 primary PLC중 PLCγ에 주목하여 최근에 밝혀진 PLCγ의 구조적 특징과 조절 기전, 그리고 질병과 관련된 돌연변이와 knockout 마우스를 활용한 연구 결과에 대해 고찰하고자 한다.

성능/효과

한편 GABAergic neuron에서의 PLCγ1 결함은 노화에 따른 간질 발작에 더 높은 감수성을 나타내었다[25]. Knockout 마우스의 Hippocampus subregions에서 inhibitory synapses가 감소하고 inhibitory synaptic transmission도 억제됨으로써 hypoactivity가 나타나고 anxiety가 감소했으며, fear memory 이상과 함께 handling에 의한 발작이 나타났다.
PLCγ1의 결핍은 T-세포의 발달과 활성화, tolerance에 이상을 가져왔다. T-세포의 positive selection과 negative selection 모두에 이상이 있었으며 특히 single-positive thymocyte와 peripheral T 세포의 수가 감소했다. 또한 TCR에 의한 ERK, JNK, AP-1, NFAT, NF-κB의 활성화가 이뤄지지 못했으며 그 결과 proliferation과 cytokine 생산이 정상적으로 이루어지지 않았다.
또한 TCR에 의한 ERK, JNK, AP-1, NFAT, NF-κB의 활성화가 이뤄지지 못했으며 그 결과 proliferation과 cytokine 생산이 정상적으로 이루어지지 않았다. 또한 FoxP3⁺ regulatory T 세포의 발달이 정상적으로 이루어지지 않으면서 염증과 자가면역질환의 양상이 나타났다.
또한 TCR에 의한 ERK, JNK, AP-1, NFAT, NF-κB의 활성화가 이뤄지지 못했으며 그 결과 proliferation과 cytokine 생산이 정상적으로 이루어지지 않았다.
하지만 ovariectomy에 의한 bone 감소에는 영향을 미치지 않았고 폐경에 의한 골다공증에는 PLCγ2가 관여하지 않아 기저상태에서와는 다른 PLCγ2를 거치지 않는 조절 기전이 존재함을 보여주었다.

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저자의 다른 논문 :

표제어: PCR

동의어: Packet Collision Rate

용어 설명 출처 목록 (6)

용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

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