第四類酪胺酸磷酸水解酶 (protein tyrosine phosphatase 4A, ptp4a) 可影響細胞的生長、分裂、移動及分化，且多表現於發育中的組織，因在腫瘤組織中表現量高，近年來研究當作癌症的生物標誌物。無脊椎動物中僅以一種形態存在 (PRL-1)，演化為脊椎動物後分為三型 (ptp4a1、ptp4a2和ptp4a3)。三型 ptp4a 間的胺基酸序列相似度很高，本論文研究的脊椎動物斑馬魚，其中 ptp4a1和ptp4a2 有 81% 相似。以原位雜交法觀察斑馬魚胚胎時期 mRNA 的表現，ptp4a1 於12小時至三天的表現量最高，多表現於腦部 (包括終腦、間腦、中腦、小腦和後腦)、眼睛 (包括視網膜色素上皮層、外叢層、內叢層和神經纖維層)、耳包、鰭等部分。而 ptp4a2 則是在胚囊期至三天的表現量均高，大部份表現於心肌、肌節、肝臟、腸道、原腎管、氣動管、鰾、鰭、下顎及眼睛的水晶體外圈等位置。接著利用顯微注射反股寡核苷酸 (morpholino) 的方式，抑制內生性 ptp4a1 和 ptp4a2 轉譯。個別抑制 ptp4a1 和 ptp4a2 可觀察到基因缺陷後造成圍心腔腫大及細胞堆積的情形，同時抑制 ptp4a1 和 ptp4a2 外觀上的缺陷更加顯著。以F59 標記抗體及 cmlc2 探針觀察心臟肌肉，可知基因缺失會造成心臟肌肉形狀改變。從基因缺失會造成細胞增生訊號下降，但沒有細胞凋亡訊號產生等結果推測，ptp4a1 和 ptp4a2 缺失會造成細胞增生受阻，以至於心臟肌肉無法正常發育，心肌折疊不完全，產生心肌畸形。此外，ptp4a1 和 ptp4a2 缺失還會導致斑馬魚感覺器官，側線神經節發育異常，無法如同野生種發育出完整的側線神經節。由上述的實驗結果可知，ptp4a1 和 ptp4a2 在脊椎動物斑馬魚身上表現位置不同， ptp4a1 多表現於腦及眼睛，ptp4a2 表現於肌肉和心臟、肝臟、腸道等多種內臟組織中。胚胎時期若 ptp4a1 和 ptp4a2 缺陷，會影響到細胞增生以至於心臟肌肉發育不完全，且影響細胞移動能力，導致側腺神經節發育異常。由此可知，ptp4a1 和 ptp4a2 對斑馬魚胚胎的發育，是重要的環節之一。

Protein tyrosine phosphatase 4A (ptp4a) family not only affect cell growth, division, migration and differentiation but serve as a “biomarker” of cancer in recent studies. Instead of only one type (PRL-1) in vertebrates, ptp4a family contains three members (ptp4a1, ptp4a2, and ptp4a3) with high sequence similarities. In this study, we focused on zebrafish ptp4a1 and ptp4a2 genes sharing 81% similarity. We performed in situ hybridization to observe the expression of ptp4a1 and ptp4a2 during zebrafish embryonic development. ptp4a1 was abundant from 12-hpf to 3-dpf, and mainly found in brain (tectum, tegmentum, telencephalon, diencephalon, mesencephalon, cerebellum, and metencephalon), eyes (retinal pigment epithelium, iris, outer plexiform layer, inner plexiform layer and nerve fiber layer), otic vesicle, and fin. On the other hand, ptp4a2 was abundant from 1-cell stage to 3-dpf, and was mainly distributed in myocardium, liver, fin, gut, myotomes, pronephric duct, pneumatic duct, swim bladder, arch and the outer region of the lens. Upon injection of antisense morpholino (ptp4a1-MO or ptp4a2-MO), pericardial edema and cell accumulation were observed in ptp4a1 or ptp4a2 knockdown embryos. Furthermore, co-injection of ptp4a1-MO and ptp4a2-MO resulted in even more significant defect. Heart malformation was revealed in ptp4a1/2 double knockdown embryos, based on immunostaining with muscle-specific F59 antibody and in situ hybridization with heart-specific cmlc2 probe. On the other hand, ptp4a1/2 double knockdown would result in disrupted neuromast development. In addition, such knockdown would decrease cell proliferation, but not lead to apoptosis. In summary, ptp4a1 and ptp4a2 showed differential expression patterns in zebrafish embryos: ptp4a1 was mainly found in brain and eyes, whereas ptp4a1 was mainly observed in muscle, heart, liver, gut and internal organs. Our knockdown data revealed that ptp4a1 and ptp4a2 affected cell proliferation and migration, leading to defects in zebrafish heart and neuromast development.

授權書
口試委員審議通過簽名單
謝誌-----------------------------------------------------------------------------I
中文摘要----------------------------------------------------------------------II
英文摘要---------------------------------------------------------------------III
目錄---------------------------------------------------------------------------IV
圖表目錄-------------------------------------------------------------------VIII
第一章 前言------------------------------------------------------------------1
1-1酪胺酸磷酸水解酶(protein tyrosin phospatase genes, PTPs)------------------1
1-2第四類酪胺酸磷酸水解酶(protein tyrosin phospatase 4A, ptp4a)-----------2
1-3第四類酪胺酸磷酸水解酶的結構------------------------------------------------3
1-4第四類酪胺酸磷酸水解酶在正常組織中的表現------------------------------4
1-5第四類酪胺酸磷酸水解酶在腫瘤及病變組織中的表現---------------------7
1-6第四類酪胺酸磷酸水解酶的表現及影響細胞週期--------------------------11
1-7第四類酪胺酸磷酸水解酶在發育中的角色-----------------------------------15
1-8斑馬魚為模式物種研究第四類酪胺酸磷酸水解酶的優勢-----------------16

第二章 材料與方法--------------------------------------------------------18
2-1斑馬魚胚胎收集 (Embryo collection)------------------------------------------18
2-2斑馬魚放缸飼養 (Fish breeding)------------------------------------------------18
2-3斑馬魚胚胎固定、脫水、保存 (Embryo fixation)------------------------------18
2-4斑馬魚胚胎 RNA 的萃取及cDNA的合成-----------------------------------19
2-5勝任細胞 (Competent cell) 的製備---------------------------------------------20
2-6細胞轉形作用(Transformation)--------------------------------------------------21
2-7小量質體萃取 (Isolation of Plasmid DNA)------------------------------------21
2-8聚合酶鏈鎖反應 (Polymerase Chain Reaction, PCR)------------------------22
2-9核酸的接合反應 (DNA ligation)------------------------------------------------22
2-10合成探針 (Riboprobe)-----------------------------------------------------------23
2-11原位雜交法 (Whole-mount in situ hybridization)---------------------------24
2-12抗體染色 (Immunostaining)----------------------------------------------------25
2-13 TUNEL Assay---------------------------------------------------------------------27
2-14側線神經節活體螢光染色------------------------------------------------------28
2-15顯微注射實驗 (Morpholino antisense oligouncleotide injection for knockdown) ------------------------------------------------------------------------------28
2-16樣品包埋及切片 (Embedding and Cryosectioning)-------------------------29
2-17顯微照相系統及序列分析軟體------------------------------------------------29

第三章 結果-----------------------------------------------------------------30
3-1斑馬魚的 ptp4a 胺基酸序列比對及演化分析圖----------------------------30
3-2各時期之斑馬魚胚胎以原位雜交法 (whole-mount in situ hybridization) 確定ptp4a1 的訊號表現位置--------------------------------------------------------32
3-3各時期之斑馬魚胚胎以原位雜交法確定ptp4a2的訊號表現位置--------35
3-4透過顯微注射 ptp4a1 & ptp4a2 morpholino 抑制 ptp4a1 & ptp4a2 的轉譯所造成之影響------------------------------------------------------------------------37
3-5 ptp4a1 & ptp4a2 morpholino 注射後的存活率及變異率-------------------38
3-6以F59免疫抗體染色法探討 ptp4a1 & ptp4a2 knockdown 後，對心臟肌肉造成的影響---------------------------------------------------------------------------40
3-7以 cmlc2 mRNA 探針，進行原位雜交法探討 ptp4a1 & ptp4a2 knockdown 後對心臟造成的影響---------------------------------------------------40
3-8以TUNEL Assay探討 ptp4a1&ptp4a2 knockdown對細胞凋亡的影響---------------------------------------------------------------------------------------------42
3-9以 Phospho-Histone H3 抗體染色探討 ptp4a1 & ptp4a2 knockdown 對細胞增生的影響------------------------------------------------------------------------43
3-10 ptp4a1 & ptp4a2 knockdown 對斑馬魚胚胎側線神經節的影響--------44

第四章 討論-----------------------------------------------------------------46
4-1 ptp4a1 & ptp4a2 於脊椎動物中具有高度保留性---------------------------46
4-2 ptp4a1 & ptp4a2 缺失導致斑馬魚胚胎的側線與心臟發育不良之可能原因------------------------------------------------------------------------------------------48
4-3 ptp4a1 & ptp4a2 影響細胞移動之可能原因---------------------------------51
4-4 ptp4a1 & ptp4a2 影響細胞生長之可能原因---------------------------------53
4-5 總結----------------------------------------------------------------------------------54

第五章 參考文獻-----------------------------------------------------------56
圖表---------------------------------------------------------------------------62
附錄---------------------------------------------------------------------------87

圖表目錄
圖一 . 斑馬魚的 ptp4a 基因體結構圖。------------------------------------------63
圖二 . 斑馬魚的 ptp4a 胺基酸序列比對及演化樹分析圖。------------------64
圖三 . 四細胞至三天大之斑馬魚以原位雜交法確定ptp4a1 的訊號表現位置。-----------------------------------------------------------------------------------------67
圖四 . 四天至七天大之斑馬魚以原位雜交法確定ptp4a1 的訊號表現位置。----------------------------------------------------------------------------------------------68
圖五 . 四細胞至三天大之斑馬魚以原位雜交法確定ptp4a2 的訊號表現位置。-----------------------------------------------------------------------------------------69
圖六 . 四天至七天大之斑馬魚以原位雜交法確定ptp4a2 的訊號表現位置。----------------------------------------------------------------------------------------------70
圖七 . 斑馬魚各個時期以原位雜交法後，以flat mount 及冷凍切片比較 ptp4a1和ptp4a2的訊號表現位置。--------------------------------------------------71
圖八 . 斑馬魚胚胎之野生種 (WT) 、ptp4a1 morphant、ptp4a2 morphant 及 ptp4a1+ ptp4a2 morphant 的表現型。-----------------------------------------------74
圖九 . 斑馬魚胚胎之F59免疫抗體染色觀察心臟表現型態。-----------------76
圖十 . 斑馬魚胚胎之cmlc2 mRNA 探針觀察心臟變異。----------------------77
圖十一 . 斑馬魚胚胎進行 TUNEL Assay，觀察細胞凋亡的情況。----------80
圖十二 . 斑馬魚胚胎之 Phospho-Histone H3 抗體染色，觀察細胞增生的情況。-----------------------------------------------------------------------------------------81
圖十三 . 斑馬魚胚胎之 RHE487 側線染色，觀察側線生長狀況。----------82
表一. 斑馬魚的 ptp4a1、ptp4a2、 ptp4a3 及果蠅的 PRL-1 之胺基酸序列相似性。-----------------------------------------------------------------------------------83
表二. 斑馬魚的 ptp4a1 與不同種類動物之胺基酸序列相似性。------------83
表三. 斑馬魚的 ptp4a2 與不同種類動物之胺基酸序列相似性。------------83
表四. 斑馬魚的 ptp4a3 與不同種類動物之胺基酸序列相似性。------------84
表五. 斑馬魚之 ptp4a1 / ptp4a2/ ptp4a3與脊椎動物間的統整總表。--------85
表六. 斑馬魚胚胎注射不同濃度之ptp4a1和ptp4a2反股寡核苷酸(morpholino antisense oligonucleotides)的存活率及變異率。--------------------86
附錄
附表一、ptp4a 表現於腫瘤組織。--------------------------------------------------88
附圖一、負回饋抑制 p53 的兩種路徑。--------------------------------------------89

Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Osterman, A., Godzik, A., et al. (2004). Protein tyrosine phosphatases in the human genome. Cell, 117(6), 699-711.
Bardelli, A., Saha, S., Sager, J. A., Romans, K. E., Xin, B., Markowitz, S. D., et al. (2003). PRL-3 expression in metastatic cancers. Clinical Cancer Research, 9(15), 5607.
Calogero, A., Arcella, A., De Gregorio, G., Porcellini, A., Mercola, D., Liu, C., et al. (2001). The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas. Clinical Cancer Research, 7(9), 2788.
Cates, C. A., Michael, R. L., Stayrook, K. R., Harvey, K. A., Burke, Y. D., Randall, S. K., et al. (1996). Prenylation of oncogenic human PTP protein tyrosine phosphatases. Cancer letters, 110(1-2), 49-55.
Chena, Y. H., Chioub, C. H., Chena, W. L., Jhoub, Y. R., Leea, Y. T., & Chengb, C. C. Rhodamine-Ethylenediol, A Novel Vital Fluorescent Probe for Labelling Alkaline Phosphatase-Rich Organelles. J. Chin. Chem. Soc, 57(6), 1.
Daoud, S. S., Munson, P. J., Reinhold, W., Young, L., Prabhu, V. V., Yu, Q., et al. (2003). Impact of p53 Knockout and Topotecan Treatment on Gene Expression Profiles in Human Colon Carcinoma Cells. Cancer research, 63(11), 2782.
den Hertog, J., Groen, A., & van der Wijk, T. (2005). Redox regulation of protein-tyrosine phosphatases. Archives of biochemistry and biophysics, 434(1), 11-15.
Diamond, R. H., Cressman, D. E., Laz, T. M., Abrams, C. S., & Taub, R. (1994). PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Molecular and cellular biology, 14(6), 3752.
Diamond, R. H., Peters, C., Jung, S. P., Greenbaum, L. E., Haber, B. A., Silberg, D. G., et al. (1996). Expression of PRL-1 nuclear PTPase is associated with proliferation in liver but with differentiation in intestine. American Journal of Physiology- Gastrointestinal and Liver Physiology, 271(1), 121.
Fagerli, U. M., Holt, R. U., Holien, T., Vaatsveen, T. K., Zhan, F., Egeberg, K. W., et al. (2008). Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood, 111(2), 806.
Fiordalisi, J. J., Keller, P. J., & Cox, A. D. (2006). PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer research, 66(6), 3153.
Fontemaggi, G., Kela, I., Amariglio, N., Rechavi, G., Krishnamurthy, J., Strano, S., et al. (2002). Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses. Journal of Biological Chemistry, 277(45), 43359.
Han, H., Bearss, D. J., Browne, L. W., Calaluce, R., Nagle, R. B., & Von Hoff, D. D. (2002). Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer research, 62(10), 2890.
Hunter, T. (2000). Signaling-2000 and beyond. Cell, 100(1), 113-128.
Jeong, D. G., Kim, S. J., Kim, J. H., Son, J. H., Park, M. R., Lim, S. M., et al. (2005). Trimeric structure of PRL-1 phosphatase reveals an active enzyme conformation and regulation mechanisms. Journal of molecular biology, 345(2), 401-413.
Kadambi, V. J., Lorenz, J. N., Stagliano, N. E., Matter, W. F., Wang, X. S., Bloem, L., et al. (2000). Impaired ventricular relaxation resulting from cardiac-specific overexpression of a human prenylated protein tyrosine phosphatase (abstract 1312). Circulation, 102.
Kato, H., Semba, S., Miskad, U. A., Seo, Y., Kasuga, M., & Yokozaki, H. (2004). High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer. Clinical Cancer Research, 10(21), 7318.
Kim, K. A., Song, J. S., Jee, J. G., Sheen, M. R., Lee, C., Lee, T. G., et al. (2004). Structure of human PRL-3, the phosphatase associated with cancer metastasis. FEBS letters, 565(1-3), 181-187.
Kong, W., Swain, G. P., Li, S., & Diamond, R. H. (2000). PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues. American Journal of Physiology- Gastrointestinal and Liver Physiology, 279(3), 613.
Kozlov, G., Cheng, J., Ziomek, E., Banville, D., Gehring, K., & Ekiel, I. (2004). Structural insights into molecular function of the metastasis-associated phosphatase PRL-3. Journal of Biological Chemistry, 279(12), 11882.
Lee, J. O., Yang, H., Georgescu, M. M., Di Cristofano, A., Maehama, T., Shi, Y., et al. (1999). Crystal Structure of the PTEN Tumor Suppressor:: Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association. Cell, 99(3), 323-334.
Lyon, M. A., Ducruet, A. P., Wipf, P., & Lazo, J. S. (2002). Dual-specificity phosphatases as targets for antineoplastic agents. Nature Reviews Drug Discovery, 1(12), 961-976.
Matter, W. F., Estridge, T., Zhang, C., Belagaje, R., Stancato, L., Dixon, J., et al. (2001). Role of PRL-3, a Human Muscle-Specific Tyrosine Phosphatase, in Angiotensin-II Signaling* 1. Biochemical and biophysical research communications, 283(5), 1061-1068.
Min, S. H., Kim, D. M., Heo, Y. S., Kim, H. M., Kim, I. C., & Yoo, O. J. (2010). Downregulation of p53 by phosphatase of regenerating liver 3 is mediated by MDM2 and PIRH2. Life sciences, 86(1-2), 66.
Min, S. H., Kim, D. M., Heo, Y. S., Kim, Y. I., Kim, H. M., Kim, J., et al. (2009). New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53. Oncogene, 28(4), 545-554.
Navis, A. C., Van Den Eijnden, M., Schepens, J. T. G., Hooft van Huijsduijnen, R., Wesseling, P., & Hendriks, W. (2010). Protein tyrosine phosphatases in glioma biology. Acta Neuropathologica, 119(2), 157-175.
Nusslein-Volhard, C., & Dahm, R. (2002). Zebrafish: a practical approach.
Park, H., Jung, S. K., Jeong, D. G., Ryu, S. E., & Kim, S. J. (2008). Discovery of novel PRL-3 inhibitors based on the structure-based virtual screening. Bioorganic & medicinal chemistry letters, 18(7), 2250-2255.
Parker, B. S., Argani, P., Cook, B. P., Liangfeng, H., Chartrand, S. D., Zhang, M., et al. (2004). Alterations in vascular gene expression in invasive breast carcinoma. Cancer research, 64(21), 7857.
Pathak, M. K., Dhawan, D., Lindner, D. J., Borden, E. C., Farver, C., & Yi, T. (2002). Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Molecular cancer therapeutics, 1(14), 1255.
Peng, L., Ning, J., Meng, L., & Shou, C. (2004). The association of the expression level of protein tyrosine phosphatase PRL-3 protein with liver metastasis and prognosis of patients with colorectal cancer. Journal of cancer research and clinical oncology, 130(9), 521-526.
Peng, Y., Du, K., Ramirez, S., Diamond, R. H., & Taub, R. (1999). Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Journal of Biological Chemistry, 274(8), 4513.
Peng, Y., Genin, A., Spinner, N. B., Diamond, R. H., & Taub, R. (1998). The gene encoding human nuclear protein tyrosine phosphatase, PRL-1. Journal of Biological Chemistry, 273(27), 17286.
Radke, I., Gotte, M., Kersting, C., Mattsson, B., Kiesel, L., & Wulfing, P. (2006). Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer. British journal of cancer, 95(3), 347-354.
Rouleau, C., Roy, A., St Martin, T., Dufault, M. R., Boutin, P., Liu, D., et al. (2006). Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Molecular cancer therapeutics, 5(2), 219.
Ruan, F., Lin, J., Wu, R. J., Xu, K. H., Zhang, X. M., Zhou, C. Y., et al. (2009). Phosphatase of regenerating liver-3: a novel and promising marker in human endometriosis. Fertility and sterility.
Rundle, C. H., & Kappen, C. (1999). Developmental expression of the murine Prl-1 protein tyrosine phosphatase gene. Journal of Experimental Zoology Part A: Comparative Experimental Biology, 283(6), 612-617.
Saha, S., Bardelli, A., Buckhaults, P., Velculescu, V. E., Rago, C., Croix, B. S., et al. (2001). A phosphatase associated with metastasis of colorectal cancer. Science, 294(5545), 1343.
Schwering, I., Brauninger, A., Distler, V., Jesdinsky, J., Diehl, V., Hansmann, M. L., et al. (2003). Profiling of Hodgkin’s Lymphoma Cell Line L1236 and Germinal Center B Cells: Identification of Hodgkin’s Lymphoma–specific Genes. Molecular Medicine, 9(3-4), 85.
Stephens, B. J., Han, H., Gokhale, V., & Von Hoff, D. D. (2005). PRL phosphatases as potential molecular targets in cancer. Molecular cancer therapeutics, 4(11), 1653.
Takano, S., Fukuyama, H., Fukumoto, M., Kimura, J., Xue, J. H., Ohashi, H., et al. (1996). PRL-1, a protein tyrosine phosphatase, is expressed in neurons and oligodendrocytes in the brain and induced in the cerebral cortex following transient forebrain ischemia. Molecular Brain Research, 40(1), 105-115.
Wang, J., Kirby, C. E., & Herbst, R. (2002). The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. Journal of Biological Chemistry, 277(48), 46659.
Wang, Y., Li, Z. F., He, J., Li, Y. L., Zhu, G. B., & Zhang, L. H. (2007). Expression of the human phosphatases of regenerating liver (PRLs) in colonic adenocarcinoma and its correlation with lymph node metastasis. International journal of colorectal disease, 22(10), 1179-1184.
Werner, S. R., Lee, P. A., DeCamp, M. W., Crowell, D. N., Randall, S. K., & Crowell, P. L. (2003). Enhanced cell cycle progression and down regulation of p21Cip1/Waf1 by PRL tyrosine phosphatases. Cancer letters, 202(2), 201-211.
Wu, X., Zeng, H., Zhang, X., Zhao, Y., Sha, H., Ge, X., et al. (2004). Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. American Journal of Pathology, 164(6), 2039.
Yarovinsky, T. O., Rickman, D. W., Diamond, R. H., Taub, R., Hageman, G. S., & Bowes Rickman, C. (2000). Expression of the protein tyrosine phosphatase, phosphatase of regenerating liver 1, in the outer segments of primate cone photoreceptors. Molecular Brain Research, 77(1), 95-103.
Yu, L., Kelly, U., Ebright, J. N., Malek, G., Saloupis, P., Rickman, D. W., et al. (2007). Oxidative stress-induced expression and modulation of Phosphatase of Regenerating Liver-1 (PRL-1) in mammalian retina. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1773(9), 1473-1482.
Zeng, Q., Dong, J. M., Guo, K., Li, J., Tan, H. X., Koh, V., et al. (2003). PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer research, 63(11), 2716.
Zeng, Q., Hong, W., & Tan, Y. H. (1998). Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. Biochemical and biophysical research communications, 244(2), 421-427.
Zeng, Q., Si, X., Horstmann, H., Xu, Y., Hong, W., & Pallen, C. J. (2000). Prenylation-dependent association of protein-tyrosine phosphatases PRL-1,-2, and-3 with the plasma membrane and the early endosome. Journal of Biological Chemistry, 275(28), 21444.
Zhou, H., Gallina, M., Mao, H., Nietlispach, D., Betz, S. F., Fetrow, J. S., et al. (2003). Letter to the Editor: 1H, 13C and 15N resonance assignments and secondary structure of the human protein tyrosine phosphatase, PRL-2. Journal of Biomolecular NMR, 27(4), 397-398.
Zon, L. I., & Peterson, R. T. (2005). In vivo drug discovery in the zebrafish. Nature Reviews Drug Discovery, 4(1), 35-44.