SH2B1β 透過促進 FGF1 之訊息傳遞與增加 FGFR1 之表現進而增強 FGF1 所誘導之神經軸突生長

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研究生：	林偉帆 Wei-Fan Lin
論文名稱：	SH2B1β 透過促進 FGF1 之訊息傳遞與增加 FGFR1 之表現進而增強 FGF1 所誘導之神經軸突生長 SH2B1β enhances fibroblast growth factor 1(FGF1)-induced neurite outgrowth through promoting FGF1 signaling and increasing FGF receptor 1 expression
指導教授：	陳令儀 Linyi Chen
口試委員:
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	80
中文關鍵詞：	SH2B1β蛋白、纖維母細胞生長因子1 、纖維母細胞生長因子接受器1 、大鼠腎上腺髓質嗜鉻細胞瘤、神經軸突生長
外文關鍵詞：	SH2B1β, FGF1, FGFR1, PC12 cells, ERK1/2, STAT3, Egr1, neurite outgrowth
相關次數：	點閱：3 下載：0
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Fibroblast growth factor 1 (FGF1) has been shown to involve in many biological processes. According to genetic studies, FGF1 signaling and FGF1-induced gene expressions as well as morphological differentiation are important during embryonic development. FGF1 induces neurite outgrowth of the rat pheochromocytorma cells (PC12 cells), and stimulates PC12 cells to differentiate into the sympathetic neuron-like cells. In this thesis, we found that overexpressing a signaling adapter protein, SH2B1β, enhances FGF1-induced neurite outgrowth in PC12 cells. SH2B1β has previously been shown to promote nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF)-induced neurite outgrowth. Interestingly, SH2B1β prolongs the NGF and GDNF-induced signaling, but not enhances these signalings. In addition, recently studies have suggested that SH2B1β is able to constitutively undergo nucleocytoplasmic shuttling in PC12 cells, revealing its putative role in transcriptional regulation. Along this line, SH2B1β has been shown to enhance the expression of a subset of NGF-responsive genes. To delineate how SH2B1β promotes the FGF1-induced neurite outgrowth in PC12 cells, we examined its role in FGF1 signaling. We demonstrated that SH2B1β, unlike NGF and GDNF-induced signaling, promotes FGF1-induced neurite outgrowth through enhancing and prolonging the MEK-ERK1/2-STAT3 signaling pathway. SH2B1β also enhances the MEK-dependent expression of immediate early gene, Egrl. Moreover, we provided the evidence that overexpression of SH2B1β in PC12 cells results in significant increasing the expression of FGFR1, suggesting that SH2B1β-enhanced neurite outgrowth is mainly via FGFR1. Taken together, these results provide the first evidence that SH2B1β enhances FGF1-induced neurite outgrowth through enhancing FGF1-induced signaling pathway and increasing the gene expression of FGFR1.

纖維母細胞生長因子一 (fibroblast growth factor 1, FGF1) 在細胞的生長發育中是重要的生長因子。從基因層面的相關研究得知，纖維母細胞生長因子之訊息傳遞與其調控之基因表現在胚胎發育過程中扮演極其重要的角色。FGF1會誘導大鼠腎上腺髓質嗜鉻細胞瘤細胞株 (rat pheochromocytoma cell line, 以下簡稱PC12 細胞) 的神經軸突生長 (neurite outgrowth) 進而分化成類交感神經細胞。先前的研究發現一訊息接合蛋白 SH2B1□□會調控神經生長因子 (nerve growth factor, NGF) 與神經膠細胞源神經營養因子 (glial-derived neurotrophic factor, GDNF) 所誘導之神經分化。其中 SH2B1β 會延長 NGF 與 GDNF 所誘導的訊息傳遞，但不會增加訊號的強度。此外 SH2B1β 也被證實能來回穿梭於細胞質與細胞核之間 (nucleocytoplasmic shuttling) 以及調控一些受 NGF 活化之基因的表現。為了進一步研究 SH2B1β 調控神經軸突生長的機制，SH2B1β 被大量表現在 PC12 細胞中。在以 FGF1 處理 PC12 細胞後，SH2B1β 會增強 FGF1 所誘導之訊息傳遞途徑─MEK-ERK1/2-STAT3 的訊號，並且延長其訊號，進而促進 FGF1 誘導 PC12 細胞的神經軸突生長。其中 MEK-ERK1/2-STAT3 的訊號在 FGF1 誘導 PC12 細胞神經軸突生長中是必要的。不僅如此，SH2B1β 也會透過增強 MEK-ERK1/2-STAT3 之訊息途徑，進而增加 MEK-ERK1/2 下游的 immediate early gene─Egr1 的表現。此外在 PC12 細胞中大量表現 SH2B1β 被發現會大量增加纖維母細胞生長因子接受器一 (FGFR1) 的表現量。此結果顯示 SH2B1β 會透過調節 FGFR1 的表現量進而增強 FGF1 誘導的神經軸突生長。總結以上的結果，本論文研究證實了 SH2B1β 會透過調控 FGF1 的訊息傳遞及 FGFR1 的基因表現進而調控 FGF1 所誘導的神經軸突生長。

List
Abstract    i
中文摘要    ii
List    iii
Abbreviations    vi
Introductions    1
Materials and Methods    11
Reagents    11
Cell culture    12
Inhibitor assay and neurite outgrowth of PC12 cells    13
Preparation of cell lysate    13
Determination of protein concentration    14
Western blot analysis    15
Immunofluorescence staining    16
Total RNA preparation    17
Reverse transcription and semi-quantitative real time polymerase chain reaction    18
Results    20
SH2B1β promotes FGF1-induced neurite outgrowth    20
SH2B1β enhances and prolongs FGF1 signaling    20
Phosphorylation of ERK1/2 is required for FGF1-induced neurite outgrowth while AKT signaling is important for maintaining neuronal phenotype    22
FGF1-induced STAT3 phosphorylation is through MEK-ERK1/2 pathway    23
SH2B1β enhances and prolongs FGF1-induced Egr1 expression    25
SH2B1β increases the expression of FGFR1    26
Working models for the SH2B1β-mediated enhancement of FGF1-induced neurite outgrowth    28
Discussions    29
References    33
Figures    42
Figure 1. Neurite outgrowth in PC12 cells overexpressing GFP (PC12-GFP) or GFP-SH2B1b (PC12-SH2B1β) after FGF1 treatment.    43
Figure 2. The phosphorylation level of ERK1/2 in PC12-GFP and PC12-SH2B1β cells after FGF1 or NGF treatment.    45
Figure 3. The effect of low dosage of FGF1 on phosphorylation level of ERK1/2 and neurite outgrowth in PC12-GFP and PC12-SH2B1β cells.    46
Figure 4. The phosphorylation level of AKT in PC12-GFP and PC12-SH2B1β cells after FGF1 or NGF treatment.    48
Figure 5. Effect of U0126 and LY294002 on FGF1 signaling and FGF1-induced neurite outgrowth in PC12-GFP and PC12-SH2B1β cells.    50
Figure 6. SH2B1β enhances phosphorylation level of S727 but not Y705 of STAT3 during FGF1 treatment through MEK-ERK pathway.    52
Figure 7. SH2B1β enhances FGF1-induced expression level of Egr1 without obvious effect on the expression level of p35.    53
Figure 8. Basal mRNA level of FGFR1, but not FGFR3 is up-regulated by SH2B1β and intracellular protein sequence of rat-FGFR1 and mouse-FGFR3 are conserved on two tyrosine residue important for SH2B1β binding through its SH2 domain.    55
Figure 9. Working models of how SH2B1β enhances FGF1-induced neurite outgrowth in PC12 cells.    57
Figure 10. General domain structure of FGF and FGFR.    58
Figure 11. The intracellular signaling pathways of FGF/FGFR during embryonic development.    59
Figure 12. Structure of FGFR1 coding exons showing locations of regions coding for three possible IgIII domains.    60
Figure 13. Model of the FGF-FGFR-HS signaling complex.    61
Figure 14. Schematic of SH2B family members.    62
Tables    63
Table 1. The members of the FGF family and their cognate FGFRs.    63
Table 2. Reverse transcription protocol used in this thesis    64
Table 3. Reaction temperature and time of reverse transcription    65
Table 4. Sequences of the Q-PCR primers used in this thesis    66
Table 5. Reaction temperature and time of Q-PCR    67
Appendix    68
Figure A1. Comparison of mRNA level of cell cycle-related genes in PC12-GFP, PC12-SH2B1β, and PC12-SH2B1β(R555E) cell lines after NGF treatment    74
Figure A2. Comparison of the mRNA level of cyclin D1 in PC12-GFP cells and PC12-SH2B1β cells particular in serum-free or serum-containing media after NGF treatment    76
Figure A3. Comparison of the protein level of cyclin D1 in PC12-GFP cells and PC12-SH2B1β cells particular in serum-free or serum-containing media during NGF treatment    77
Figure 4A. Compared to distributions of three cell phases, G0/G1, S, and G2/M, in PC12-GFP, PC12-SH2B1β, and PC12-SH2B1β(R555E) cells.    79

                                

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