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研究生:郭津岑
研究生(外文):Jean-Cheng Kuo
論文名稱:探討DAPK在細胞骨架及細胞移動之調控分析
論文名稱(外文):Functional Characterization of DAPK in cytoskeleton regulation and cell migration
指導教授:陳瑞華陳瑞華引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:124
中文關鍵詞:死亡相關蛋白激酶細胞集中附著點壓力纖維細胞極性
外文關鍵詞:DAPKstress fiberintegrincell polarity
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死亡相關蛋白激酶(Death-associated protein kinase,DAPK)是一個受鈣╱攜鈣素所調控的絲胺酸╱酪胺酸激酶。先前的研究顯示其參與許多細胞凋亡及腫瘤抑制作用,但其間機制至今仍未清楚。在這份論文的第一個部份,我們証明了DAPK可以藉由磷酸化肌凝蛋白II的調節輕鏈(regulatory light chain of myosin II,MLC)在絲胺酸19位置,進而穩定壓力纖維(stress fiber)的生成。除此之外,當細胞在沒有血清的培養條件下,表現DAPK對細胞集中附著點(focal adhesion)而言,並不能刺激其形成;當我們重新加入血清去刺激,DAPK的存在對細胞集中附著點(focal adhesion)而言,非但不能刺激其形成反倒是促使其消失但是對壓力纖維確沒有影響。我們推測這樣一種對細胞壓力纖維和集中附著點消長間不協調的作用機制,結果會抑制細胞的附著(cell adhesion)能力進而誘使細胞凋亡的進行。在論文的第二個部份,我們則著重在探討DAPK的腫瘤抑制功能。先前的證據顯示,DAPK主要是經由其誘發細胞凋亡的作用來達到腫瘤抑制。DAPK所造成的細胞凋亡是p53-dependent,但在大多數的腫瘤細胞中其p53確是沒有作用的。如此一來,顯示DAPK尚存在有另一種作用機制來造成腫瘤抑制。基於DAPK的功能在會調控細胞骨架蛋白和胞外基質受器(integrin)活性,因細胞骨架蛋白和胞外基質受器在細胞移動的能力上均扮演著重要的角色,我們推測DAPK會影響細胞的移動。我們發現表現DAPK會減弱細胞極性(polarization),藉由干擾細胞對方向性的持續力和移動力進而抑制了細胞的隨機移動(random migration)。這些DAPK對細胞移動能力的影響也被証實的確是因為DAPK抑制了胞外基質受器/cdc42的訊號傳遞。更在p53沒有作用的腫瘤細胞中證明,雖然表現DAPK並不會造成這類細胞的死亡,但當DAPK表現時還是會抑制其細胞的移動和侵入能力,更進一步證明DAPK在抑制腫瘤上的角色。最後,利用一對來源相同、卻具不同侵入能力的肺癌上皮細胞株,我們發現了DAPK的表現量和其細胞的侵入能力具有相當程度的負相關。這更進一步證實DAPK參與了p53-independent的腫瘤抑制功能。
總括來說,在探討DAPK如何執行其細胞生理功能上,我們証明DAPK會經由磷酸化肌凝蛋白II的調節輕鏈來影響細胞壓力纖維的穩定,同時並造成與細胞集中附著點形成之間作用的不協調。如此,對DAPK所參與的細胞凋亡過程上有重要性的影響。我們也找到DAPK一個p53-independent的作用機制,DAPK會藉由影響細胞的移動能力來造成腫瘤抑制功能。
Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase. Its functions in pro-apoptosis and tumor suppression have been studied before, but detailed mechanism isn’t fully elucidated. In the first part of the study, we demonstrate that DAPK is capable of phosphorylating the regulatory light chain of myosin II (MLC) at serine 19 in vitro and in vivo, resulting in stress fibers stabilization. However, DAPK cannot stimulate the formation of focal adhesion in quiescent cells and promotes the disassembly of focal adhesions but not stress fibers in cells receiving serum factors. Thus, we proposed that DAPK functions in the uncoupling of stress fibers and focal adhesions. Such uncoupling would lead to a perturbation of the balance between contractile and adhesion forces and subsequent cell detachment, which might contribute to its pro-apoptotic activity. In the second part of the study, we focus on the mechanism through which DAPK functions as a tumor suppressor. DAPK is thought to execute tumor suppressive function by its apoptotic activity. However, the apoptotic effect of DAPK is largely p53-dependent, while many tumor cells are p53 defective. To reconcile this, we tested whether DAPK has another mechanism to suppress tumor. As DAPK has been demonstrated to the regulate cytoskeleton and integrin activity, both of which play a role in cell migration, we therefore study the function of DAPK in migration. We found that DAPK inhibits random migration by reducing directional persistence and directed migration by blocking cell polarization. These DAPK-mediated migratory defects are mainly through its suppression of integrin/Cdc42 pathway. The regulation of migration by DAPK indeed in part explains for its tumor suppressor function, exemplified by the fact that in certain p53-mutant tumor cells that are resistant to DAPK-induced apoptosis, DAPK expression can still block their migratory and invasive abilities. Furthermore, by using a paired of lung adenocarcinoma cell lines, which are of the same source but of different invasive activities, we demonstrated that DAPK expression level is a determinant factor in tumor invasiveness. There emerges the second, p53-independent, mechanism for DAPK in tumor suppression. To sum up, to get insight how DAPK exerts its physiological function, we demonstrate that DAPK uncouples stress fibers and focal adhesions, partly through its phosphorylation of MLC. Besides, we uncover a new p53-independent mechanism mediated by DAPK to affect cell motility, accounting for its tumor suppressive functions.
CONTENTS 1
ABSTRACT 5
中文摘要 6
LITERATURE REVIEW 7
1. MIGRATION 7
1.1 The Phenomena of Cell Migration 7
1.2 The Migration Cycle 7
2. CELL POLARITY 8
2.1 The Phenomena of Cell Polarity 8
2.2 The Molecular Mechanism in Cell Polarization 8
2.2.1 Regulation of actin cytoskeleton during directed migration 8
2.2.2 Regulation of microtubule during directed migration 9
2.2.3 Positive feedback interactions between microtubule and actin dynamics 11
2.3 Role of integrin in cell polarization 11
3. CYTOSKELETON REORGANIZATION 13
3.1 The function of myosin II and the phosphorylation of myosin light chain (MLC) 13
3.2 The molecular regulation of MLC phosphorylation 13
3.2.1 Myosin phosphatase 13
3.2.2 Myosin light chain kinases 14
3.2.3 Phosphorylation at other sites of MLC 15
3.3 The roles of MLC phosphorylation in physiological condition 16
3.3.1 The morphological change, either in the central portion or in the peripheral portion of a cell, in response to actomyosin contractility 16
3.3.2 Cytokinesis 17
3.3.3 The formation of apoptotic membrane blebbing 18
4. TUMOR METASTASIS 19
4.1 The Process of Tumor Metastasis 19
4.2 The Role of Integrin in Tumor Progression 19
5. DEATH-ASSOCIATED PROTEIN KINASE (DAPK) 21
5.1 The Overview of DAPK 21
5.1.1 The Multi-domain Structure of DAPK 21
5.1.2 Expression Pattern of DAPK 21
5.1.3 The catalytic regulation of DAPK 22
5.2 The Role of DAPK in Tumor Suppression 23
5.2.1 The Pro-Apoptotic Activity of DAPK 23
5.2.2 The Tumor Suppressive Function of DAPK 24
CHAPTER I 25
UNCOORDINATED REGULATION OF STRESS FIBERS AND FOCAL ADHESIONS BY DAP KINASE 25
ABSTRACT 25
INTRODUCTIONS 26
MATERIALS AND METHODS 29
Plasmids 29
Antibodies and reagents 29
Cell culture, transfection and retroviral infection 29
Production of baculovirus 30
Immunoprecipitations and in vitro kinase assays 30
Preparation of detergent-soluble and insoluble fractions 30
Phosphoamino acid analysis 31
Immunofluorescence 31
Reduction of endogenous DAP-kinase expression using siRNA 31
Interference reflection microscopy 31
RESULTS 33
DAP kinase phosphorylates MLC in vitro and in vivo 33
DAP kinase stabilizes stress fibers in quiescent cells 34
Effect of DAP kinase on F-actin does not require its death domain and is not a consequence of apoptosis 35
DAPK and MLCK play distinct roles in the assembly of actin filaments 36
DAP kinase mediates serum-induced stress-fiber formation 37
DAP kinase does not stimulate focal-adhesion assembly 38
DAPK triggers disassembly of focal adhesions but not stress fibers in cells receiving serum growth factors 39
DISCUSSIONS 41
CHAPTER II 44
THE TUMOR SUPPRESSOR DAPK INHIBITS CELL MOTILITY BY BLOCKING INTEGRIN-MEDIATED POLARITY PATHWAY 44
ABSTRACT 44
INTRODUCTIONS 45
MATERIALS AND METHODS 48
Plasmids 48
Antibodies and Reagents 48
Cell culture, transfection and retroviral infection 48
Time-lapse recording 49
Analysis of cell migration 49
Immunofluorescence 50
Flow cytometry analysis 51
Preparation of GST-PBD fusion protein 51
Cdc42 activity assay 52
Knockdown of endogenous DAPK by siRNA 52
RESULTS 53
DAPK inhibits random cell migration by reducing directional persistence 53
DAPK inhibits directed migration by interfering with cell polarization. 54
DAPK blocks Cdc42 activation in response to migration cues. 54
DAPK suppresses cell polarization through integrin inactivation. 55
The integrin activator talin rescues the directionality and polarity defects induced by DAPK. 56
Endogenous DAPK is observed to be localized at the leading edge of migrating cells. 56
DAPK suppresses migration and invasion of tumor cells that are resistant to its pro-apoptotic effect. 57
DAPK functions as a determining factor in tumor cell invasion. 58
Endogenous DAPK suppresses cell polarization during directed migration 59
DISCUSSION 60
CONCLUSION 64
FIGURES 66
Fig. 1. DAPK phosphorylates MLC in vitro and in vivo. 66
Fig. 2. DAPK promotes the assembly or stabilization of stress fibers. 68
Fig.3. DAPK stabilizes stress fibers through MLC phosphorylation. 70
Fig. 4. Maintenance of stress fibers by DAPK does not require its death domain. 71
Fig. 5. DAPK and MLCK display distinct roles in the assembly of stress fibers. 73
Fig. 6. DAPK is involved in serum-induced stress fiber formation. 75
Fig. 7. DAPK is required for serum-induced stress fiber formation and is activated by serum. 77
Fig. 8. DAPK does not stimulate the formation of focal adhesions. 79
Fig. 9. DAPK can not promote the assembly or maintenance of focal adhesions. 81
Fig. 10. IRM analysis shows the inability of DAPK to induce focal adhesion assembly. 83
Fig. 11. DAPK promotes focal adhesion disassembly under serum-stimulated conditions. 85
Fig. 12. IRM analysis shows DAPK promotes focal adhesion disassembly under serum-stimulated conditions. 87
Fig. 13. DAPK does not affect stress fibers under serum-stimulated conditions. 89
Fig. 14. Effects of DAPK on migration path, rate, distance and directional persistence of free-moving fibroblasts. 90
Fig. 15. Effects of DAPK on wound-healing migration. 92
Fig. 16. DAPK interferes with cell polarization during wound-healing migration. 93
Fig. 17. DAPK disrupts cell polarity by blocking wounding-induced Cdc42 activation. 95
Fig. 18. Activation of integrin β1 rescues DAPK-induced migratory defects. 97
Fig. 19. Activation of integrin rescues the defects in random and directed migrations induced by DAPK. 99
Fig. 20. GFP-talin rescues the motility defects of DAPK. 101
Fig. 21. Intracellular localization of endogenous DAPK is observed at the leading edge in migrating cells. 103
Fig. 22. DAPK inhibits migration and invasion of two p53-defective tumor cell lines without triggering apoptosis. 104
Fig. 23. DAPK inhibits tumor cells migration without triggering apoptosis. 106
Fig. 24. DAPK expression level is a determining factor of tumor invasion. 108
SUPPLEMENTAL MOVIES 110
Supplemental Movie 1: Time-lapse videomicroscopy monitoring the free-moving NIH3T3 cells carrying vector or various DAPK proteins. 110
Supplemental Movie 2-5: Time-lapse videomicroscopy monitoring the wound-healing migration of NIH3T3 cells carrying vector (Movie 2), wild type DAPK (Movie 3), DAPKdCaM (Movie 4) or DAPK42A (Movie 5). 110
Supplemental Movie 6: Time-lapse videomicroscopy monitoring the free-moving NIH3T3 derivatives treated with 9EG7. 110
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