磷酸化蛋白 Collapsin response mediator protein-2 (CRMP-2) 具備調節神經軸突生長以及調控微小管動態活動 (microtubule dynamics) 的功能。過去的研究發現在愛滋海默症 (Alzheimer's disease) 病變的腦組織中，CRMP-2 呈現異常的高度磷酸化狀態，而且愛滋海默症的病程發展 (pathogenesis) 與磷酸化激酶 glycogen synthase kinase-3 (GSK-3) 的活性變化有關。一般認為 CRMP-2 只存在於神經組織中，然而實際上有關 CRMP-2 於非神經細胞中的表現情形仍未有清楚結論。本論文中，我運用西方墨點法 (Western blotting) 以及反轉錄酶-聚合酶連鎖反應法 (RT-PCR) 證明 CRMP-2 不僅存在於神經細胞中，亦表現於非神經細胞之中。CRMP-2 於不同的細胞株呈現不同的表現量，且其蛋白含量似乎與細胞的惡性 (malignancy) 程度有關。我同時於人類神經細胞以及非神經細胞中發現一個全新的 CRMP-2 亞型 (variant)，稱為長型 CRMP-2 (the long form of CRMP-2, CRMP-2L)。我運用人類基因資料庫 (human genomic database) 推測出人類 CRMP-2L 的互補去氧核醣核酸 (cDNA) 序列，至於 CRMP-2L 於人類細胞中的實際表現情形亦以西方墨點法以及反轉錄酶-聚合酶連鎖反應法加以確認。就筆者所知，本論文為證實長型 CRMP-2 表現於人類細胞中的首次報導。
CRMP-2 為磷酸化蛋白 (phosphoprotein)。本論文中，我們在豬腦萃取物當中發現 CRMP-2 是 GSK-3 的主要受質之一。GSK-3 家族的兩種亞型 (isoform) 酵素，包括 GSK-3 及 GSK-3 皆能有效地對由豬腦中所純化出的 CRMP-2 進行磷酸化作用，且顯著地延遲 CRMP-2 在膠體電泳中的移動速度；而此一現象與愛滋海默症病患腦中 CRMP-2 的修飾作用 (modification) 很相似。有趣的是，將 SK-N-SH 神經母細胞瘤 (neuroblastoma) 細胞處以去磷酸酶 (phosphatase) 抑制劑岡田酸 (okadaic acid)，可引發 CRMP-2 產生相同的修飾作用；而若事先處理 GSK-3 抑制劑，則能完全阻斷岡田酸所引發的 CRMP-2 的修飾現象。利用核醣核酸干擾法 (RNA interference) 同時降低 (knock down) GSK-3 及 GSK-3 的蛋白質表現，可以有效地削弱岡田酸所引發的 CRMP-2 的修飾作用；然而若單一降低 GSK-3 或 GSK-3 的蛋白質表現，則無此削弱作用。我們將愛滋海默症相關的 CRMP-2 高度磷酸化作用點絲胺酸-518 (Ser-518) 以及絲胺酸-522 (Ser-522) 點突變成無法被磷酸化 (non-phosphorylatable) 的丙胺酸 (alanine)，可以完全阻斷岡田酸在 SK-N-SH 細胞中所引發的 CRMP-2 的修飾現象。由試管中實驗發現， CRMP-2 在被 GSK-3 磷酸化之前，其絲胺酸-522 必須先被 cyclin-dependent kinase 5 (Cdk5) 進行事先磷酸化 (pre-phosphorylation) 作用後才能被 GSK-3 磷酸化。然而利用 Cdk5 抑制劑 roscovitine 或是核醣核酸干擾法抑制 Cdk5 的活性，對於岡田酸在細胞中所引發的 CRMP-2 的修飾現象並無法產生明顯抑制作用。綜合上述結果，本論文首次證明岡田酸可以引發 SK-N-SH 細胞中 CRMP-2 產生與愛滋海默症相關的高度磷酸化修飾作用。在此過程，GSK-3、GSK-3 以及絲胺酸-522 激酶 (kinase) 皆參與其中。

Collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in axonal outgrowth and microtubule dynamics, is aberrantly phosphorylated in Alzheimer disease (AD) brain. Alteration of glycogen synthase kinase-3 (GSK-3) activity is associated with the pathogenesis of AD. CRMP-2 is highly expressed in the developing nervous system. It is believed that CRMP-2 is a neuronal tissue-specific protein, however, its expression in non-neuronal cells has not been investigated clearly. Here I demonstrate that CRMP-2 is not only expressed in neuronal cells but also in non-neuronal cells by RT-PCR and Western blotting analyses. CRMP-2 is differentially expressed in different cell lines and the amount of CRMP-2 protein seems to correlate with the degree of malignancy. In addition, I also identify a novel variant of CRMP-2, the long form of CRMP-2 (CRMP-2L), in human neuronal and non-neuronal cells. Putative human CRMP-2L cDNA sequence was predicted from human genomic database and its expression in human cells was also confirmed. So far as I known, it is the first report that demonstrates the long form of CRMP-2 exist in human cells. I also provide evidence to show that CRMP-2 is one of the major substrates for GSK-3 in pig brain extracts. Both GSK-3 and 3 phosphorylate purified pig brain CRMP-2 and significantly alter it mobility in SDS-gels, resembling the CRMP-2 modification observed in AD brain. Interestingly, this modification can be detected in SK-N-SH neuroblastoma cells treated with a phosphatase inhibitor, okadaic acid (OA), and GSK-3 inhibitors completely block this OA-induced event. Knock-down of both GSK-3 and 3but not either kinase alone, impairs OA-induced modification of CRMP-2. Mutation of Ser-518 or Ser-522 of CRMP-2, which are highly phosphorylated in AD brain, to Ala blocks the OA-induced modification of CRMP-2 in SK-N-SH cells. Ser-522 prephosphorylated by Cdk5 is required for subsequent GSK-3-mediated hyperphosphorylation of CRMP-2 in vitro. However, inhibition of Cdk5 by roscovitine or siRNA pools has little effects on the OA-induced modification of CRMP-2 in cells. Collectively, our results demonstrate for the first time that OA can induce hyperphosphorylation of CRMP-2 in SK-N-SH cells at sites aberrantly phosphorylated in AD brain, and both GSK-3 and 3and Ser-522 kinase(s) are involved in this process.

指導教授推薦書
口試委員審定書
長庚大學授權書………………………………………………………. iii
誌謝……………………………………………………………………. iv
Abbreviations………………………………………………………….. v
中文摘要………………………………………………………………. vii
Abstract ……………………………………………………………….. ix
1. Introduction …………………………………………………………. 1
1.1 Glycogen synthase kinase-3 (GSK-3)…………………………… 1
1.1.1 GSK-3 isoforms …………………………………………… 1
1.1.2 GSK-3 regulation ………………………………………….. 3
1.1.3 GSK-3 substrates …………………………………………… 6
1.1.4 GSK-3 in Wnt signaling …………………………………… 7
1.1.5 GSK-3 in the regulation of cell polarity …………………… 10
1.1.6 GSK-3 in Alzheimer’s disease …………………………….. 11
1.2 Collapsin response mediator protein-2 (CRMP-2)……………… 14
1.2.1 CRMP-2 regulates growth cone collapse ………………….. 15
1.2.2 CRMP-2 in axon formation ………………………………… 15
1.2.3 Phosphorylation of CRMP-2 ………………………………. 16
1.2.4 CRMP-2 in Alzheimer’s disease …………………………… 17
2. Specific aims ……………………………………………………….. 19
3. Materials and methods ……………………………………………… 21
3.1 Materials ………………………………………………………… 21
3.2 Purification of enzymes and proteins …………………………… 21
3.3 Assay for substrate phosphorylation ……………………………. 22
3.4 Two-dimensional (2D) gel electrophoresis, in-gel
digestion of proteins and mass spectrometric analysis ………... 22
3.5 Production of anti-CRMP-2, anti-CRMP-2L,
anti-GSK-3 and anti-GSK-3 antibodies……………………. 23
3.6 Two-dimensional phosphoamino acid analysis ………………… 24
3.7 Cell culture, transfection, drug treatment,
Western blot and immunoprecipitation ………………………. 24
3.8 Plasmids construction…………………………………………… 25
3.9 Production of recombinant proteins …………………………...... 27
3.10 RNA interference and siRNA transfection…………………….. 28
3.11 Reverse transcriptase polymerase chain
reaction (RT-PCR)……………………………………………. 28
4. Results ……………………………………………………………… 30
4.1 Purification of a major substrate for GSK-3
from pig brain …………………………………………………. 30
4.2 Molecular weight shift of the purified substrates
in SDS-PAGE after phosphorylation by GSK-3 ……………..... 31
4.3 Identification of the purified substrates as
collapsin response mediator protein-2 (CRMP-2) …………….. 31
4.4 Long form of CRMP-2 (CRMP-2L) is found
in human cells ………………………………………………..... 33
4.5 CRMP-2 and CRMP-2L are expressed in both
neuronal and non-neuronal cell lines ………………………...... 35
4.6 Okadaic acid induces modification of CRMP-2
in human SK-N-SH neuroblastoma……………………………. 37
4.7 GSK-3 inhibitors prevent the OA-induced
phosphorylation of CRMP-2 in SK-N-SH cells ………………. 38
4.8 Identification of the major phosphorylation region
in CRMP-2 by GSK-3 is located in F3 segment …………….... 39
4.9 GSK-3 is as important as GSK-3 in OA-induced
modification of CRMP-2 in cells ……………………………… 40
4.10 Both Ser-522 and Ser-518 are required for OA-induced
phosphorylation-dependent mobility shift of
CRMP-2 in neuroblastoma cells …………………………….. 42
4.11 Prephosphorylation of CRMP-2 by Cdk5 is required
for subsequent GSK-3-catalyzed phosphorylation
and mobility shift of CRMP-2 in vitro ………………………. 42
4.12 Inhibition of Cdk5 is not sufficient to impair the
OA-induced modification of CRMP-2 in
SK-N-SH cells ……………………………………………….. 43
5. Discussion ………………………………………………………….. 45
6. References ………………………………………………………….. 54
7. Tables and figures ………………………………………………….. 74
8. Supplementary information ……………………………………....... 115
9. Appendix …………………………………………………………… 120

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