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系統識別號 U0026-1508201322354900
論文名稱(中文) MST3在癌症中所扮演的角色
論文名稱(英文) The Role of Mammalian Sterile 20-Like Kinase 3 (MST3) in Cancer
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 卓建宇
研究生(英文) Chien-Yu Cho
學號 S58951544
學位類別 博士
語文別 英文
論文頁數 71頁
口試委員 指導教授-賴明德
召集委員-呂增宏
口試委員-楊倍昌
口試委員-凌斌
口試委員-洪文俊
口試委員-戴明泓
口試委員-馬明琪
中文關鍵字 MST3  VAV2  Rac1  乳癌  EGFR  磷酸化  肺癌 
英文關鍵字 MST3  VAV2  Rac1  breast cancer  EGFR  phosphorylation  lung cancer 
學科別分類
中文摘要 MST3 (mammalian STE20-like kinase 3)屬於Ste20 serine/threonine protein kinase family。MST3所調控的下游分子包括PTP-PEST、paxillin和NDR蛋白;然而,MST3在癌症中所扮演的角色並沒被研究。一開始我們利用免疫染色發現MST3在乳癌組織中會大量表現。利用線上軟體Kaplan-Meier plotter分析顯示乳癌病人組織中大量表現MST3會有較差的存活率。利用shRNA將SK-Br-3和MDA-MB-231乳癌細胞株中的MST3降低會抑制細胞增生速度及非固著依賴性生長。此外MDA-MB-231中MST3被降低在免疫缺失小鼠的皮下會形成較小的腫瘤。為了確認MST3經由什麼途徑影響癌細胞的癌化,我們利用共同免疫沉澱及共軛焦顯微鏡發現MST3和VAV2的結合。更進一步,我們發現MST3上的多嘌呤區域會和VAV2上的SH3區域結合。野生型MST3大量表現會促進細胞增生速度及非固著依賴性生長,多嘌呤區域去除的MST3則不會。大量表現野生型MST3還會增加VAV2的磷酸化及下游分子GTP-Rac1的活化,反之降低MST3或是大量表現多嘌呤區域去除的MST3則會降低VAV2和GTP-Rac1的活化。降低MST3還會減少cyclin D1的表現量。Rac1的抑制劑EHop-016也會降低野生型MST3所誘發的cyclin D1大量表現。這些結果顯示MST3結合VAV2會活化其下游分子而促進乳癌細胞癌化。
雖然MST3上游活化因子目前也還不清楚。但我們發現在EGFR大量表現的A431細胞中,EGF會使MST3到細胞膜並誘導MST3的活化。為了測定MST3轉移到細胞膜上是否對於其酵素活性是重要的,將MST3接上myristoylation的訊息胜肽可促使MST3更容易留在細胞膜,發現會因此增加MST3的活性。利用共同免疫沉澱法發現MST3會和EGFR結合。EGFR上的Y992、Y1086和Y1148突變後則會降低和MST3的結合。我們也發現MST3上的酪氨酸殘基在EGF及去磷酸酵素抑制劑的刺激下會被磷酸化。而在試管裡的實驗發現重組蛋白EGFR會直接造成MST3上酪氨酸殘基的磷酸化。利用線上軟體預測MST3上的Y81、Y196和Y283可能會被磷酸化。將這三個位點突變後發現Y196F和Y283F會降低MST3上酪氨酸殘基的磷酸化,但只有Y196F會降低MST3的活性。相較於野生型的MST3,大量表現Y196F-和Y283F-MST3會降低AKT及ERK的活性並降低肺癌細胞生長。這些結果顯示在EGF刺激下細胞膜上的MST3會被磷酸化並活化EGFR下游分子來促進細胞生長。
英文摘要 MST3 (mammalian STE20-like kinase 3) belongs to the Ste20 serine/threonine protein kinase family. The downstream signaling includes protein tyrosine phosphatase PEST (PTP-PEST), paxillin, and nuclear Dbf2-realated (NDR) proteins; however, the role of MST3 in cancer progression has not been studied as thoroughly. Initial examination of the expression of MST3 by immunoblotting revealed overexpression of MST3 in breast cancer tissues. The online Kaplan-Meier plotter analysis revealed that overexpression of MST3 predicts poor prognosis in breast cancer patients. Expression of shMST3 inhibited proliferation and anchorage-independent growth in vitro. Downregulation of MST3 in MDA-MB-231 breast cancer cells decreased tumor formation in NOD/SCID mice. To identify the pathway through which MST3 influences tumor progression, we demonstrated, by co-immunoprecipitation and confocal microscopy, that MST3 interacted with VAV2. By truncating different domains of MST3, we determined that the proline-rich region of MST3 (353KDIPKRP359) interacted with the SH3 domain of VAV2. Overexpression of wild-type MST3 (WT-MST3), but not proline-rich-deleted MST3 (∆P-MST3), enhanced proliferation rates and anchorage-independent growth in SK-Br-3 cells. Overexpression of WT-MST3 increased VAV2 phosphorylation and GTP-Rac1 activation, whereas downregulation of MST3 and ∆P-MST3 resulted in a reduction of VAV2 and Rac1 activation. Knockdown of MST3 inhibited cyclin D1 protein expression. Rac1 inhibitor EHop-016 attenuated induction of cell proliferation and cyclin D1 by WT-MST3 in SK-Br-3 cells. These data indicated that MST3 interacted with VAV2 to induce cyclin D1 to promote the tumorigenicity of breast cancer.
The upstream activators of MST3 remain largely unknown at present,. Our study revealed that MST3 translocated to the membrane when stimulated by EGF in A431 cells. In addition, MST3 kinase activity was induced by EGF. To determine whether membrane translocation plays a role in kinase activation, MST3 was fused with myristoylation (myr) signal peptide to mimic membrane translocation, and it was found that myr-MST3 exhibits higher kinase activity than WT-MST3. Co-immunoprecipitation demonstrated that MST3 formed a complex with EGFR during EGF treatment. Mutations of Y992, Y1086, and Y1148-EGFR weakened the complex formation of EGFR and MST3. The tyrosine residues of MST3 were phosphorylated by treatment with EGF or the phosphatase inhibitor pervanadate. Recombinant EGFR directly phosphorylated MST3 in an in vitro assay. The public domain software NetPhos (ver. 2.0) predicted the phosphorylation sites of MST3 at Y81, Y196 and Y283. Mutations of these three tyrosine residues into phenylalanine revealed that Y196F and Y283F-MST3 exhibited lower tyrosine phosphorylation, but only Y196F-MST3 lost its kinase activity. Overexpression of Y196F- or Y283F-MST3 decreased pAKT and pERK and attenuated cell growth in H1299 lung cancer cells. These data suggest that the membrane location of MST3 was phosphorylated, and that it enhanced the activation of downstream pathways of EGFR to promote cell growth upon EGF stimulation.
論文目次 Contents
Abstract in Chinese………………………………………………………………......i
Abstract…………………………………………………………………………….. iii
Acknowledgement……………………………………………………………………v
Contents…………………..………………………………………………………….vi

Introduction
1. Ste20 (sterile 20) kinase family………………………………………………..01
2. Biological function and signal transduction of MST kinases……...…..……02
3. Posttranslational modifications of MST kinases………………...……...…...04
4. MST kinases and cancer…………………………………………...………….04
5. VAV family…………………………………………………………...………..05
6. Epidermal growth factor receptor………………………………..…….…….07

Research aims…………………………………………………………..…….……..09

Materials and Methods
(A) Materials
1. Chemical reagents………………………...….…………………...…………...10
2. Antibodies……………………………………………………………………...10
3. Kits……………………………………………………………………….……..11
4. Instruments……………………………………………………………….…..11
(B) Methods
1. Cell culture...…………………………………………….……….……….……12
2. Plasmids construction…………………………………………………………14
3. Western blot……………………………………………………………………15
4. Co-immunoprecipitation……………………………………………………...17
5. MST3 in vitro kinase assay……………………………………………….…...17
6. Colony formation assay…………………………………………...…….…….17
7. Anchorage-independent growth assay……………....……………………….18
8. Xenografted tumor model……………………………………...……………..18
9. Confocal immunofluorescence microscopy……….………...……….………18
10. Rac1 GTPase activity pulldown assay……………………..…….………….19
11. MST3 phosphorylation in vitro……………………………………………...19
12. Tissue samples………………………………………………………………...19
13. Statistical analysis……………………...…………………………………….20

Results
1. MST3 is overexpressed in breast cancer tissue and associated with patients survival……………………………………………..…………...……….…….21
2. Downregulation of MST3 inhibits proliferation and tumorigenicity of breast cancer cell lines………………………………………………………...……...21
3. MST3 associates with VAV2………………………….……..……….……….22
4. Proline-rich region of MST3 is required for interaction with SH3 domain of VAV2…….………………………………………………………….………...23
5. Interaction of MST3 with VAV2 enhances cell growth and activation of the VAV2-Rac1 pathway………………...……………………… ……………....23
6. MST3 induces cyclin D1 expression through the VAV2-Rac1 pathway to promote cell growth and tumorigenesis……………..………………………24
7. EGF induces MST3 to the cell membrane and enhances MST3 kinase activity………………………………………………………………...……….25
8. The interaction between MST3 and EGFR is dependent on autophosphorylation of tyrosine residues Y992, Y1086 and Y1148 in EGFR………………………………………………………………………….25
9. EGFR phosphorylated the tyrosine residues of MST3…………...............…26
10. Mutant Y196F-MST3 loses its kinase activity, and overexpression of Y196F-MST3 in H1299 cells attenuates cell growth………...……………...27

Discussion……………………………………………………………………………29

Conclusions………………………………………………………………………….34

References………………………………………………………….………………..35

Figures and Table
Figure 1. MST3 is up-regulated in breast cancer tissue………………………….41
Figure 2. High expression of MST3 correlates with survival of breast cancer patients……………………………………………………………………42
Figure 3. Attenuation of MST3 by shRNA inhibits proliferation of breast cancer cells……………………………………………………………….………..43
Figure 4. Attenuation of MST3 by shRNA inhibits tumorgenesis of breast cancer cells in vitro and in vivo……………………………………….………….44
Figure 5. MST3 interacts with VAV2 in a transfection model system…………..45
Figure 6. MST3 interacts with VAV2……………………………………………...46
Figure 7. MST3 interacts with SH3 containing domain of VAV2……………….47
Figure 8. Deletion of the proline-rich region of MST3 fails to interact with VAV2……………………………………………………………………...49
Figure 9. MST3 enhances VAV2 phosphorylation and Rac1 activation………...51
Figure 10. Overexpression of WT-MST3, but not ∆P-MST3, enhances cell proliferation and tumorgenesis………………………………………...53
Figure 11 MST3 induces cyclin D1 expression…………………………………....54
Figure 12 MST3 induces cyclin D1 through VAV2-Rac1 pathway for promoting cell growth and tumorigenesis………………………………………….55
Figure 13 EGF enhances the kinase activity of MST3…………………………...56
Figure 14 MST3 translocates to plasma membrane upon EGF stimulation…....57
Figure 15 The membrane location of MST3 enhances its kinase activity………58
Figure 16 MST3 interacts with EGFR in a transfection model system…………59
Figure 17 EGF induces the interaction between MST3 and EGFR…………….60
Figure 18 Mutant Y992F, Y1086F and Y1148F of EGFR exhibit weaker interaction with MST3………………………………………………….61
Figure 19 EGF induces phosphorylation of tyrosine residues of MST3………...62
Figure 20 EGFR directly phosphorylates the tyrosine residues of MST3……....63
Figure 21 Mutant Y196F-MST3 decreases tyrosine phosphorylation and loses its kinase activity…………………………………………………………...64
Figure 22 Overexpression of Y196F- and Y283F-MST3 decrease pAKT and pERK and attenuate cell growth in H1299 cells………………………65
Figure 23 High expression of MST3 correlates with survival of lung cancer patients…………………………………………………………………..66
Figure 24 The proposed model of MST3 function in our study…………………67
Table 1. Site-directed mutagenesis primers for mutant plasmids……………….68

Appendixes
Appendix 1. The posttranslational modifications of MST3………………………69
Appendix 2. Biological function and signal transduction of MST3……………...70
Appendix 3. Structure and activation of VAV2……………………………………71
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