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1 Journal of Life Science 2014 Vol. 24. No ~1382 The Functional Role of Phospholipase D Isozymes in Apoptosis Do Sik Min Department of Molecular Biology, Pusan National University, Busan , Korea Received August 27, 2014 /Revised September 12, 2014 /Accepted September 24, 2014 Phospholipase D (PLD) catalyzes the hydrolysis of phospholipid to phosphatidic acid (PA), a lipid secondary messenger. Two forms of PLD isozymes, phosphatidylcholine-specific PLD1 and PLD2, have been identified. PLD has emerged as a critical regulator of cell proliferation and survival signaling, and dysregulation of PLD occurs in a various illnesses, including cancer. PLD activity is essential for cell survival and protection from apoptosis. Overexpression of PLD isozymes or PLD-generated PA attenuates the expression of apoptotic genes and confers resistance to apoptosis. The apoptosis-related molecular mechanisms of PLD remain largely unknown. Recently, the dynamics of PLD turnover during apoptosis have been reported. The cleavage of PLD isozymes as specific substrates of caspase differentially regulates apoptosis. PLD1 is cleaved at one internal site, and PLD2 is cleaved two sites at the front of the N-terminus. The cleavage of PLD1 reduces its enzymatic activity, probably via the dissociation of two catalytic motifs, whereas the cleavage of PLD2 does not affect the catalytic motifs and its activity. Thus, PLD2 maintains antiapoptotic capacity, despite its cleavage. Therefore, the differential cleavage pattern of PLD isozymes by caspase affects its enzymatic activity and antiapoptotic function. Thus, PLD is considered a potential target for cancer therapy. We summarize recent studies regarding the functional role of PLD in apoptosis. Key words : Apoptosis, caspase, cleavage, expression, phospholipase D ISSN (Print) ISSN (Online) DOI : - Review - 서 포스포리파제 D (Phospholipase D, PLD) 는인지질을가수 분해시켜 phosphatidic acid (PA) 라는이차신호전달물질을 생성하는효소이다 [3, 10]. PLD 는세포의증식, 생존, 분화, 세 포골격조절등의다양한생리현상을조절하는것으로알려져 있다 [3, 10]. PLD 는미생물, 식물, 바이러스, 효모, 그리고동 물에모두존재하며, 보존된효소활성부위를가지고있다 [3]. 포유동물의경우두종류의 PLD 동위효소, PLD1, PLD2 가존 재하며, 아미노산유사성은 50% 를보여주고있다. 이들 PLD 동위효소는인지질중에서가장많이존재하는 phosphatidylcholine (PC) 을특이적인기질로이용하며, 효소활성부위 에두군데의 HKD 영역을가지고있으며이들두개의 HKD 영역이하나의효소활성부위를형성하고있다 [3]. PLD1 과 PLD2 는단백질 - 단백질상호결합에관여하는 pleckstrin homology (PH) 영역, Phox (PX) 영역과인지질인 phosphatidylinositol 4,5-bisphosphate 와결합하는영역을가지고있어세 포신호전달에중요한조절을하는것으로알려져있다 [2]. *Corresponding author *Tel : , Fax : * minds@pusan.ac.kr This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 론 PLD는다양한암조직에서과발현되어있으며 [3-8], 암세포에서 PLD의과발현은, 항암제에의한세포사멸을억제함으로써항암제내성을나타내며 [23, 2, 21]. 세포사멸과정중에 PLD 동위효소는 caspase에의해분해되면서효소활성과세포사멸이조절된다. 세포증식과항암제내성에서 PLD의역할 PLD의발현과효소활성이유방암 [22], 대장암 [35], 신장암 [37], 뇌종양 [24] 등의다양한암조직에서증가됨이보고되었으며, 세포사멸 (apoptosis) 을유도하는조건에서 PLD의과발현은세포사멸을억제한다 [17, 38]. 또한, PLD효소활성은마우스에서암유전자 Ras에의해매개되는암화과정에필요한것으로알려져있다 [3]. PLD는표피성장인자수용체 (epidermal growth factor receptor) [29] 와세포외기질분해효소 (matrix metalloproteinase, MMP) 의발현 [14], p53 [12], mtor (mammalian target of rapamycin) 그리고 Ras를포함하는암화신호전달경로에중요한역할을하는것으로알려져있다. PLD와 Ras 신호전달간경로간에는일련의복잡한신호전달네트워크가존재한다. PLD의생성산물인 PA는 Raf-1 kinase와직접결합하여세포막으로의이동을유도함으로써 Raf-1을활성화시키거나 [26], Ras의활성단백질인 SOS 에결합하여 SOS를활성화시켜 Ras-Raf 신호전달경로를활성화시키는네트워크가작동한다 [36]. PLD효소활성은세포성장신호전달, 세포사멸억제및전이과정을포함하는암화과정에서중요한역할을하는것으로알려져있다 [8]. PLD동

2 Journal of Life Science 2014, Vol. 24. No 위효소를과발현시킨세포주에항암제인 etoposide 를처리시 세포사멸을억제하는반면, 효소활성이결여된 PLD 동위효소 를과발현시켰을때에는함암제에의해유도되는세포사멸을 억제하지않는것으로보아 PLD 효소활성이항암제에대한 저항성에관여함을알수있다 [21]. Etoposide 등의항암제는 세포사멸유도단백질이나암억제단백질의발현을증가시켜 항암활성을보여주고있는데, PLD 가과발현된세포에서는 Egr-1 이라는암억제전사단백질의발현이감소되어 etoposide 에의한 Egr-1 의 transactivation 이억제됨으로써 Egr-1 의 표적유전자인 PTEN 이라는암억제유전자의발현이감소되 어있다. PLD 에의한 Egr-1 발현의억제는 PI3K/Akt 세포 생존신호전달경로를통하여이루어지며, PLD 효소활성이 Egr-1 및 PTEN 의발현을억제함으로써항암제에의한세포 사멸에대한내성인자로작용한다 [21]. 따라서, 암억제단백질 인 Egr-1 과 PTEN 이 PLD 신호전달의표적분자임을시사하고 있다. 또한, PLD 는암억제단백질인 p53 을분해시키는 MDM2 단백질의발현을증가시켜서항암제에의한세포사멸 과정에서 p53 의단백질안정성을감소시킴으로써항암제에 의한세포사멸에대한내성을유도한다 [11]. 또한, PLD 효소 활성산물인 PA 가 p53 의발현을억제하는것으로보고되었 다 [16]. 이와같이 PLD 는다양한세포사멸유도및암억제단 백질의발현을조절함으써세포사멸억제기능을나타내고있 다 (Fig. 1). 세포증식을촉진시키는다양한세포성장인자들 (PDGF, FGF, EGF) 과돌연변이에의해활성화된암유전자들 (v-ras, v-raf) 이 PLD 효소활성을증가시키며, PLD 가 mitogen-activated protein kinase (MAPK) 신호전달경로를활성화시킴 으로써세포증식을매개하고있다 [27]. PLD 활성이, 암미세환 경의저산소조건에서발현되어암세포의성장을자극하는 hypoxia inducible factor (HIF) 라는전사단백질의발현을증 가시켜신생혈관생성에관여하는 VEGF 의발현을증가시키 고혐기적대사과정으로변화시켜서암세포의생존을유리하 게도와주는데관여하고있다 [26]. Wnt 신호전달은세포증식의핵심조절인자로알려져있으 며 Wnt 신호전달경로의비정상적인활성화는암화과정을유 Fig. 1. PLD isozymes protects anticancer-induced apoptosis. Overexpression of PLD shows resistance to apoptosis via PLD-generated PA which suppresses expression of anticancer-induced proapoptotic genes and tumor suppressors. 도하는것으로잘알려져있다 [5]. Wnt 신호전달이활성화되면, β-catenin단백질이안정화되어핵내로이동하여전사인자인 TCF와결합하여표적유전자들의발현을증가시켜세포증식을촉진하게된다, 최근에, PLD1과 PLD2가 Wnt 신호전달의새로운표적유전자로서발현이증가되고 PLD효소활성이 β-catenin과 TCF와의상호결합을증가시켜 Wnt 신호전달을활성화시킨다는사실이보고되었다 [18, 19, 20]. PLD가 Wnt 에의해매개되는암세포의증식에관여하고있어 PLD와 Wnt 경로는서로활성화시키는신호전달네트워크로암화과정을촉진시키는데중요한역할을한다. mtor는세포성장을조절하는핵심단백질로서 serine/threonine kinase 활성을지니고있으며, PLD에의해생성된 PA가 mtor에결합하여 mtor를활성화시켜세포의증식을촉진하는것으로알려져있다 [7, 32]. PLD동위효소특이적인억제제는 mtor의활성을저해시켜암세포의증식을억제한다 [34]. 그래서 PLD의효소활성과발현은세포의증식과세포사멸억제기능에중요한역할을함으로써암화과정에기여할것으로여겨진다. 세포사멸에서 PLD의활성과발현프로그래밍되어있는세포사멸인 apoptosis과정중에 PLD 의활성과발현에대한결과들에대한보고가다소논쟁의여지가있었지만 [23], 최근에세포사멸중에 PLD의발현조절에관하여분자수준에대한기전이규명되었다 [16, 13, 25, 33]. PLD1과 PLD2동위효소가세포사멸과정중에활성화되는단백질분해효소인 caspase의기질로작용하여잘려진다 [13, 25, 33]. 다양한항암제를처리하여세포사멸을유도하였을때 PLD1은 caspase-1,-3, -8에의해 64 kda의 N-말단 fragment (NF-PLD1) 와 56 kda의 C-말단 fragment (CF-PLD1) 로잘려졌으며, calpain이나 cathepsin등의다른단백질분해효소에의해서는잘려지지않았다 [25]. Caspase에의해잘려지는보존된 DXXD부위를돌연변이시켜확인한결과, PLD1의 D545를 Ala으로치환하였을때 caspase에의해잘려지지않은것으로보아 caspase에잘려지는부위가 DDVD545이라는사실이규명되었다 (Fig. 2A) [25]. 또한, etoposide를처리시 PLD1 효소활성이감소되었으며, caspase-3 억제제를처리시 etoposide에의해감소된 PLD1 효소활성이회복되었다. 그러나, caspase에의해잘려지지않는 D545A-PLD1은 etoposide 에의한 PLD1효소활성의감소를보여주지않기때문에, 세포사멸과정중에 PLD1은 caspase에의해절단됨으로써 PLD1 효소활성이감소된다는사실을제시하고있다 [16]. 흥미롭게도 NF-PLD1 단독으로는세포사멸을유도하였으며, endogenous PLD1과결합하여 PLD1효소활성을억제하여암억제단백질인 p53의존적인경로를통하여세포사멸을촉진한다는분자기전이규명되었다 (Fig. 2B) [16]. PLD효소활성의억제는, p53 단백질을분해시키는 E3 ligase인 MDM2의발현을증가시킴으로써 p53의발현이증가되어세포사멸을유도하

3 1380 생명과학회지 2014, Vol. 24. No. 12 A B Fig. 2. Caspase-3-mediated cleavage sites and role of PLD isozymes during apoptosis. (A) Schematic diagrams for putative caspase-3- cleavage sites of PLD isozymes (B) During apoptosis, association of a considerable portion of the cleaved fragments of PLD1 contributes to resistance to anti-cancer drug-induced apoptosis via recovery of its enzymatic activity although a minor portion of free NF-PLD1 can induce apoptosis. Free CF-PLD1 localizes into nucleus but its function remains unknown in the nucleus. Cleavage of PLD2 induced by apoptosis still show antiapoptotic function. 게된다 [13]. 세포사멸을유도시켰을때 PLD2 또한 caspase에의해절단되지만, PLD2의 N-말단의맨앞쪽부위에존재하는 DELD16의 D (Asp) 부위에서먼저절단된후에 DEVD28부위가분해되어, 효소활성을나타내는두개의 HKD영역에는영향을주지않아 PLD2효소활성에는영향을주지않는것으로보고되었다 (Fig. 2A) [13]. 그래서, PLD동위효소의절단부위의차이가이들동위효소의활성에차이를보여주고있음을의미한다. Caspase에저항성을나타내는 PLD1은세포사멸억제효과를보여주고있는반면, PLD2는세포사멸중에절단되어도세포사멸을억제하였으며 (Fig. 2B), PLD2가 PLD1보다세포사멸에대한높은억제효과를보여주었다. 그래서 caspase에의한 PLD동위효소의차별적인분해가, 효소활성과세포사멸억제기능에영향을주고있음을시사하고있다. 흥미롭게도 CF-PLD1의 nuclear localization sequence (NLS) 에 β-importin단백질의결합을통하여핵으로이동한다는사실이규명되었지만핵내에서어떤역할을하는지에대해서는아직밝혀지지않았다 [14]. 또한, caspase에의해절단되어생기는 NF-PLD1과 CF-PLD1에는효소활성을나타내는 HKD 영역을각각한개씩함유하고있으며이들 HKD 영역안에존재하는 hydrophobic amino acids를통하여 NF-PLD1과 CF-PLD1이서로결합을하고있다 [15]. 이들의 PLD1 fragment간의결합은 PLD1의효소활성을회복하였으며세포사멸에대한억제효과를보여주고있다 [15]. 그러나이들 fragments 간의결합은, CF-PLD1의핵내로의이동을억제하였는데, 이는아마도 CF-PLFD1에존재하는 NLS가 masking되어 β-importin등이핵내로이동에필요한단백질들의결합이저해됨으로써일어나는현상으로여겨진다 [15]. 세포사멸과정중에 PLD동위효소가 caspase의새로운기질로작용하여차별적으로절단됨으로써 PLD효소활성과세포사멸이조절되는분자기전을보여주고있다. 결 PLD 는다양한암조직에서과발현되어있고항암제에대한 세포사멸에대한저항성을보여주고있으며, 세포사멸과정중 에 PLD 의효소활성과발현이세포사멸을정교하게조절하기 때문에항암제의새로운표적단백질로서의가능성이제기되 고있다. PLD 효소활성과발현에대한특이적억제제는암억 론 제효능을나타낼수있을것으로전망된다. 감사의글 이논문은부산대학교자유과제학술연구비 (2 년 ) 에의하여 연구되었음. References 1. Ahn, M. J., Park, S. Y., Kim, W. K., Cho, J. H., Chang, B. J., Kim, D. J., Ahn, J. S., Park, K. and Han, J. S A single nucleotide polymorphism in the phospholipase D1 gene is associated with risk of non-small cell lung cancer. Int J Biomed Sci 8, Bruntz, R. C, Taylor, H. E., Lindsley, C. W. and Brown, H. A Phospholipase D2 mediates survival signaling through direct regulation of Akt in glioblastoma cells. J Biol Chem 289, Buchanan, F. G., McReynolds, M., Couvillon, A., Kam, Y., Holla, V. R., Dubois, R. N. and Exton, J. H Requirement of phospholipase D1 activity in H-RasV12-induced transformation. Proc Natl Acad Sci USA 102, Chen, Y., Rodrik, V. and Foster, D. A Alternative phospholipase D/mTOR survival signal in human breast cancer cells. Oncogene 24,

4 Journal of Life Science 2014, Vol. 24. No Clevers, H Wnt/beta-catenin signaling in development and disease. Cell 127, Dhingra, S., Rodriguez, M. E., Shen, Q., Duan, X., Stanton, M. L., Chen, L., Zhang, R. and Brown, R. E Constitutive activation with overexpression of the mtorc2-phospholipase D1 pathway in uterine leiomyosarcoma and STUMP: morphoproteomic analysis with therapeutic implications. Int J Clin Exp Pathol 4, Foster, D. A Phosphatidic acid signaling to mtor: signals for the survival of human cancer cells. Biochim Biophys Acta 1791, Foster, D. A. and Xu, L Phospholipase D in cell proliferation and cancer. Mol Cancer Res 1, Gozgit, J. M., Pentecost, B. T., Marconi, S. A., Ricketts- Loriaux, R. S., Otis, C. N. and Arcaro, K. F PLD1 is overexpressed in an ER-negative MCF-7 cell line variant and a subset of phospho-akt-negative breast carcinomas. Br J Cancer 97, Huang, P. and Frohman, M. A The potential for phospholipase D as a new therapeutic target. 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Carcinogenesis 30, Riebeling, C., Bourgoin, S. and Shields, D Caspase cleavage of phospholipase D1 in vitro alters its regulation and reveals a novel property of the "loop" region. Biochim Biophys Acta 1781, Rizzo, M. A., Shome, K., Watkins, S. C. and Romero, G The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras. J Biol Chem 275, Selvy, P, E., Lavieri, R. R., Lindsley, C. W. and Brown, H. A Phospholipase D: enzymology, functionality, and chemical modulation. Chem Rev 111, Shen, Q., Stanton, M. L., Feng, W., Rodriguez, M. E., Ramondetta, L., Chen, L., Brown, R. E. and Duan, X Morphoproteomic analysis reveals an overexpressed and constitutively activated phospholipase D1-mTORC2 pathway in endometrial carcinoma. Int J Clin Exp Pathol 4, Snider, A. J, Zhang, Z., Xie, Y. and Meier, K. 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5 1382 생명과학회지 2014, Vol. 24. No. 12 central role of the FRB domain in small molecule-mediated regulation of mtor. Oncogene 27, Wright, M. H., Farquhar, M. J., Aletrari, M. O., Ladds, G. and Hodgkin, M. N Identification of caspase 3 motifs and critical aspartate residues in human phospholipase D1b and phospholipase D2a. Biochem Biophys Res Commun 369, Xu, L., Salloum, D., Medlin, P. S., Saqcena, M., Yellen, P., Perrella, B. and Foster, D. A Phospholipase D mediates nutrient input to mammalian target of rapamycin complex 1 (mtorc1). J Biol Chem 286, Yamada, Y., Hamajima, N., Kato, T., Iwata, H, Yamamura, Y., Shinoda, M., Suyama, M., Mitsudomi, T., Tajima, K., Kusakabe, S., Yoshida, H., Banno, Y., Akao, Y., Tanaka, M. and Nozawa, Y. J Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer. J Mol Med 81, Zhao, C., Du, G., Skowronek, K., Frohman, M. A. and Bar- Sagi, D Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9, Zhao, Y., Ehara, H., Akao, Y., Shamoto, M., Nakagawa, Y., Banno, Y., Deguchi, T., Ohishi, N., Yagi, K. and Nozawa, Y Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem Biophys Res Commun 278, Zhong, M., Shen, Y., Zheng, Y., Joseph, T., Jackson, D. and Foster, D. A Phospholipase D prevents apoptosis in v-src-transformed rat fibroblasts and MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 302, 초록 : 세포사멸에서 Phospholipase D 동위효소의기능적역할민도식 ( 부산대학교자연과학대학분자생물학과 ) Phospholipase D (PLD) 는세포막을구성하는주요지질인인지질을분해하여, 이차신호전달물질인 phosphatidic acid (PA) 를생성함으로써세포의성장및증식, 생존신호전달등세포내다양한생리현상을조절하는중요한신호전달핵심단백질로대두되고있다. PLD의비정상적인발현과활성은다양한암을비롯한여러질환에서나타난다. PLD에의해생성된 PA는세포사멸유전자의발현을감소시켜서세포사멸에대한내성을나타내고있다. 최근에, 세포사멸과정에서 PLD 단백질의 turnover dynamics에관한분자수준에서의연구가규명되었다. PLD는, 세포사멸시활성화되는단백질분해효소인 caspases의새로운기질로작용하여세포사멸을차별적으로조절을한다. Caspase에의한 PLD동위효소의차별적인분해양상이 PLD의효소활성과세포사멸억제기능을조절한다. 그래서 PLD는암치료의표적분자로서의가능성이제시된다. 본리뷰논문에서, 세포사멸조절 PLD의기능적역할에대해서술하고자한다.

2016 학년도약학대학면접문제해설 문제 2 아래의질문에 3-4분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세

2016 학년도약학대학면접문제해설 문제 2 아래의질문에 3-4분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세 본문제에대한지적소유권은동국대학교에있습니다. 본교의서면허락없이무단으로출판, 게재, 사용할수없습니다. 문제 2 2016 학년도약학대학면접문제 아래의질문에 3-4 분이내로답하시오. 표피성장인자수용체 (epidermal growth factor receptor, EGFR) 는수용체티로신 인산화효소군 (receptor tyrosine kinases, RTKs) 의일종으로서세포의생존과증식