Midkine in Tumorigenesis and Tissue Regeneration

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1 ISSN CN ΠQ Chinese Journal of Biochemistry and Molecular Biology (12) : , 3 (,, ) (midkine,mk).,mk.,. MK,, MK,,,,. MK. MK, ; ; ; ; Q71 Midkine in Tumorigenesis and Tissue Regeneration DU Li2Juan, HAN Wei 3 ( Regenerative Medicine Laboratory, School of Pharmacy, Shanghai Jiaotong University, Shanghai , China) Abstract Midkine (MK) is one of the heparin2binding growth factors that strongly expressed during embryogenesis, where the level and distribution is restricted in adults. Multiple kinds of MK receptors attribute to its various functions via different downstream signaling pathways. MK has an anti2apoptotic activity and is known to promote the growth, survival, differentiation and migration of many cell types. It is vigorously involved in development and regeneration of normal tissues, as well as in tumorigenesis. In this review, we will illustrate MK from the aspects of molecular structure, receptors, related signaling pathways, biological functions, and mechanisms of its activities. Key words midkine ; anti2apoptosis ;tumorigenesis ;tissue regeneration ;signaling pathways Midkine ( MK) 1988 Kadomatsu HM21 cdna,,, MK,,., (midkine),, (midgestation) (kidney). MK,,.,,MK,,,,.,MK,.,MK MK., MK, MK. : , : (No. 05DZ19319) 3 Tel : ,E2mail edu. cn Received : June 12,2007 ; Accepted : September 26, 2007 Supported by Scientific Technology Research Foundation from Shanghai Science and Technology Committee (No. 05DZ19319) 3 Corresponding author Tel : ,E2mail edu. cn

2 MK,, PTP ALK LRP ( integrins ) (syndecans) C(neuroglycan C,NGC), MK.,,,MK. 1 MK MK 2 Hox 412, MK 11 p2, 5 4,,. N,, C. MK,, MK. MK WT1 (Wilm 21) (5 2GCGGGGGCG23 ), WT1,MK,, MK 21 (AP1) [1,2 ]. cdna,mk N,, MK 1 20, MK 13 kd, 121,, 10, 5, MK 87 %,, N 3. MK, 121. MK N C 2, N, C., 3 [3 ]. MK MK C, C. C 3, 2, 1 2 3, Lys 76 Arg 78 Lys 99,, MK MK PTP. 2 3, Lys 83 Lys 84 Arg 86.,2 C,, MK MK 3,. MK,, C.,C 13 MK,C.,C [4 ]. MK,97 5 min 1 molπl,. MK, MK, MK [5 ]. 2 MK MK,,. MK ( Fig11). MK., MK (protein tyrosine phosphatase, PTP ) (anaplastic lymphoma kinase, ALK) (LDL receptor2related protein, LRP). PTP, 1,,. PTP MK K d 0156 nmolπl,, K d 818 nmolπl,, PTP MK. PTP MK, [6,7 ]. ALK, MK K d 170 pmolπl,mk ALK [8 ]. LPR, MK,,LPR MK [9 ],MK LPR K d 315 nmolπl.

3 12 : 983 Fig. 1 The signal receptor complex of midkine ( MK) Six receptors for MK and their possible signaling pathways are proposed. For neuroglycan C and integrins as functional receptors of MK, their downstream signaling pathways are still not clear, further studies are needed to clarify the precise mechanism. These receptors might be differentially utilized for specific biological activities of MK, or might cooperate with each other to enhance intracellular signals. The functional interaction and complex formation between these receptors remain to be clarified, (syndecans) MK, MK., NGC(neuroglycan C) MK. MK,., MK,. MK MK MK, MK.,,, ( extracellular signal2regulated kinase, ERK),ERK (mitogen2activated protein kinase, MAPK) 1..,, 3 (phosphatidylinositol 32kinase, PI3K)., caspase23, caspase23,. MK caspase23,. ERK ERK,MK caspase23.,caspase23 ERK.,MK ERK, ERK caspase23,.,c2jun N (JNK) MAP 1,, MK JNK,. MAP, MK PI3, ERK caspase23. PI3,Src PI3,, MK PTP LRP, src PI3 [8 ]., MK,,,MAPK PI3K MK. MK, PTP LRP, ( 4 12 and 6 12integrins), MK [10 ].,. MK LRP, K d 315 nmolπl. PTP LRP MK, MK,.,. MAP,, MK MK [11 ]. PDGF

4 984 23, MK,,.,, Rho G PI3 MAP ( Erk 1 Erk 2) C. MAP ( Erk 1 Erk 2),.,MK.,MK,PTP MK, MK PTP, Src PI3, MAP MK, WI238 (HUVEC) ALK,MK ALK, PI3 MAP. MK ALK, [9 ].,MK 200 kd (p200 + Π MKR), K d 0107 nmolπl, MK MK. MK p200 + ΠMKR,,MK2 JAK 1 JAK 2, JAK 1 JAK 2 STAT 1, JAKΠSTAT [12 ]., MK, MK MK MK,,.. PDGF A PDGF B FGF ( nuclear localization signal, NLS),NLS. MK, NLS, MK. MK LRP LBP. LRP LDL. LRP, (nucleolin) MK. MK LRP,,,,NLS MK. LRP MK,, MK, MK [10 ]., 37 kd ( laminin2 binding protein precursor, LBP) MK. MK LBP,, LBP, MK [13 ] MK NGC,NGC MK,. MK CG24,CG24 NGC. NGC,. NGC MK E (chondroitin sulfate E, CS2E),, NGC MK., MK,NGC,., NGC, MK,NGC MK [14 ] MK,MK (LRP). MK

5 12 : 985 ; LRP, LRP,.,., 3 d,mk ; 5 d, MK ; 14 d, MK.,MK,.,MK., C2jun mrna,c2jun 21 (AP21), MK AP21,,MK. LRP MK, MK,. MK LRP MK, [6 ]. 3 MK 3. 1 MK,MK,., MK. MK., MK. ( HCC), HCC., (AFP), 1Π3 HCC AFP, AFP., HCC., 218 HCC, 5 ( GPC3 PEG10 MDK S ERPINI1 QP2C), HCC, AFP., AFP, HCC MK, MK HCC., MK AFP, HCC [15 ].,, MK., MK.,, Wilm MK, MK,, MK., MK (MK2AS), ( HCC), MK2AS 52 (52Fu), (AFP), Western MK p53 Bax Bcl22 caspase23 5.,,MK2AS HCC,. MK2AS 52Fu AFP,, MK2 AS Bcl22, p53 Bax caspase23 3.,MK2AS, Western, p53 Bax caspase23, Bcl22.,MK2AS [16 ].,,MK2AS [17 ]., MK., MK, MK, DOX, Hep G 2., MK Hep G2., 2 DOX Hep G 2., MK DOX [18 ].

6 986 23,MK,. MK, MK,,MK,. MK. MK, (CMV)., CMV 2,, MK CMV 2,. MK 213 kb, MK CMV2, [19 ]. MK, MK., MK, PCR MK., B (B2ALL), MK.,MK B,MK B [20 ].,MK, T ( T2ALL),,WT 1 T2ALL B2ALL.,MK WT 1,WT 1 MK MK, MK WT 1 (ALL).,MK B,MK, MK, MK., PCR,MK CD ;,MK.,MK? MK MK,, MK [21 ].,MK, MK.,MK [22 ].,, (MK ),. PCR, MK.,MK, 24 h [23 ].,MK,,.,MK, MK. MK cdna ATDC5 MK,.,MK, [24 ]., MK,,MK, MK 9N2 3N1 Saos22 NOS21,, 25 % 65 %.,MK [25 ]. 4,MK, MK., MK MK.,MK,

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