Chinese Journal of Biochemistry and Molecular Biology. Effect of IL KAP on Tumorigenesis and Tumor Development

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1 ISSN CN ΠQ Chinese Journal of Biochemistry and Molecular Biology IL KAP (6) : ), 2), 1), 1) 3 ( 1), ; 2), ) ( ILKAP) 2C( PP2C),,. ILKAP,. ILKAP,. ILKAP, c2jun Π (JNKΠMAPK).,, ILKAP, ILKAP,. ; 2C ; ; Q556 Effect of IL KAP on Tumorigenesis and Tumor Development ZHOU Wang 1), GUAN Ke2Xing 2), ZOU Xue 1), ZHANG Ying2Jiu 1) 3 ( 1) Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun , China ; 2) College of Life Sciences, Jilin Agricultural University, Changchun , China) Abstract ILKAP ( integrin2linked kinase2associated phosphatase) is a novel member of PP2C (protein phosphatase 2C) family. The results have revealed that IL KAP is an apoptosis2associated phosphatase. IL KAP is ubiquitously expressed in human tissues, especially in skeletal muscle, liver and kidney ones. IL KAP plays a major physiological role in the regulation on cellular apoptosis, and involved in the suppression of the tumorigenesis and tumor development. IL KAP played its role mainly based on the integrin and JNKΠMAPK (c2 J un N2terminal kinaseπmitogen2activated protein kinase) signaling pathways. On the other hand, the loss of heterozygosity of IL KAP gene has been confirmed in many tumor tissues. Moreover, we noted that a truncated isoform of ILKAP by Splice2Site Mutations of ILKAP gene also existed in many tumor tissues, which failed to suppress the tumorigenesis and tumor development. Key words ILKAP ; PP2C ; tumor ; apoptosis,.,,,.,,. ( integrin2linked kinase2associated phosphatase, ILKAP).,.,. ILKAP 1 (integrin2linked kinase21, ILK21), 1 (apoptosis signal2regulating kinase 1, ASK1) Thr845 JNKΠMAPK : ; : (No. 2006) 3 Tel : ; E2mail : edu. cn Received : February 11,2009 ; Accepted : March 17, 2009 Supported by Project Sponsored by the Scientific Research Foundation, State Education Ministry for the Returned Overseas Chinese Scholars (No. 2006) 3 Corresponding author Tel : ; E2mail : edu. cn

2 ,, ILKAP,, ILKAP, ILKAP,. ILKAP ILKAP,, ILKAP ; ILKAP, N. 1 IL KAP 1998,Tong [1 ], C 2C ( protein phosphatase 2C, PP2C), PP2C PP2C 30 %, N 76., ILKAP, ILKAP, Fig11 (A) : N, PP2C. ILKAP,Tong PP2C, PP2C. 2001,Leung2Hagesteijn [2], 1(Ilk21), PP2C, PP2C Ilk21, PP2C (ILKAP).,ILKAP. Fig. 1 Structure scheme and PP2C domain of IL KAP (A) Two 2sheet lamellar form a flat lamellar space structure in the center of ILKAP, its active site is located at the top of the spatial structure of the opening ; (B) The active site of ILKAP and its mutation in tumor tissues. ILKAP mutations are concentrated in its N terminal, and can not express the activity ILKAP 2 IL KAP ILKAP PP2C, 44 kd, 392, N 76 C PP2C, Fig11 (A). Northern, ILKAP,,, [1 ]. ILKAP, 95 % 95 % 97 %, Fig12 (A). ILKAP PP2C PP2C,PP2C,PP2C PP2C 31 % 29 % 38 %,

3 6 : ILKAP 491 PP2C PP2C PP2C 78 %. 37 %,PP2C PP2C 37 % Fig12 (B). N 76, ILKAP., ILKAP N ILKAP,. ILKAP C PP2C, PP2C 11, ILKAP Π, Fig11 (B). Fig. 2 Homology analysis of IL KAP (A) Homology analysis of the PP2C2like domain of ILKAP among human, mouse and rat. The PP2C2like domain of ILKAP from human body share 95 % sequence identity with those from rat and mouse, while it is 97 % between rat and mouse ; (B) Homology analysis of the PP2C2like domain in ILKAP, PP2C, PP2C and PP2C. The PP2C2like domain of ILKAP share 31 %,29 % or 38 % sequence identity with the PP2C, PP2C or PP2C, respectively, and PP2C does 78 % or 37 % sequence identity with PP2C or PP2C, while it is 37 % sequence identity between PP2C and PP2C D1,. PP2C,,ILKAP Ilk21 Mg 2 + Mn 2 + [3 ], [15 ]. ILKAP, Mn 2 + Mg 2 +, Ilk21, Ilk21 [4 ]. PP2C,, Ilk21 ILKAP, [2 ]. ILKAP. Kumar [16 ] [5 ] [6., H 2 O ] 2, (LNCaP), [7 ] PP2C. ILKAP Ilk21,,ILKAP Mn 2 +, Mg 2 +, GSK23. RNA Mg 2 + [1 ]. ILKAP Mg 2 + ILKAP, cyclin D1. PP2C 3 IL KAP (integrin signaling pathway) 20.,., [8 10 ]. Ilk21. 2 B (protein kinase B,PKB) 3 (glycogen synthase kinase 3,GSK23 ). Ilk21 PKB Ser473, PKB,, [11 ]. Ilk21 GSK23 Ser9, ( 2catenin), C2Myc ( cellular myelocytomatosis oncogene,c2myc) D1 (cyclin D1), [12,13 ]., ILK21,,, ILK21., ILK21, ILK21, Ilk21 3 [14 ]. ILKAP Ilk21,, Fig13. Leung2Hagesteijn, Ilk21 ILKAP,, GSK23, 2 catenin, C2Myc ILKAP LNCaP,

4 Fig. 3 Apoptosis regulation of IL KAP in integrin signaling and JNK signaling pathways ILKAP activity inhibits ILK2 GSK3 signaling, suggesting that ILKAP activity inhibits oncogenic transformation. ILKAP also associated with ASK1, activating this kinase by enhancing the phosphorylation of Thr845. These observations suggest that ILKAP might act as a positive regulator of TNF 2induced apoptosis G 1, RNA ILKAP, S. ILKAP, LNCaP,. Kumar,ILKAP GSK23,, ILKAP [16 ]. 4 IL KAP JNK c2jun ( c2jun N2terminal kinase, JNK) 1990 (mitogen2activated protein kinase,mapk), Π [17 ]. JNK JNK ( ).,JNK,. JNK., JNK [18 20 ].JNK. JNKΠSAPK,. 1 (apoptosis signal2regulating kinase 1,ASK1) JNKΠSAPK. ASK1 Thr845,, JNKΠSAPK., JNKΠSAPK, ILKAP ASK1 Thr845 [21 ]. ILKAP ASK1, JNKΠSAPK,, Fig13. ASK1 Thr845, ILKAP ASK1 (Ser83 Ser967 Ser1034) [22,23 ]. 5 IL KAP,,, (loss of heterozygosity LOH), 2,. LOH,. 2007, Cengiz [24 ] 2q21237, ILKAP.,, ILKAP. ILKAP, ILKAP, ILKAP, ILKAP cdna, ILKAP. Trizol RNA, cdna, PCR, PCR pucm2t.., ILKAP, N 44, 77 ( GenBank, FJ491380) ; ILKAP, N 96

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