Abstract
During neurogenesis, cell adhesion and neurotrophic signaling play important
roles in each differentiation stages. SH2B family proteins were identified as
adaptor proteins which contain multiple domains, and these proteins were known to
participate in various cellular responses. In this thesis, we present novel functions
of two adaptor proteins, SH2B1β and SH2B3. We provide evidence suggesting that
overexpression of SH2B1β, reduces N□cadherin levels and increased phosphotyrosine
654 β□catenin, leading to increased nerve growth factor□induced neurite initiation in
PC12 cells. These findings provide significant new insights into how
N□cadherin□mediated inter□cellular interactions may influence neurite initiation and
how SH2B1β may regulate these processes.
Among SH2B family members, SH2B3 was shown to play an inhibitory role for
immune system development. Its role in neuronal differentiation is not known.
We provide evidence showing that overexpression of SH2B3 not only inhibits
NGF□induced differentiation of PC12 cells but also reduces neurite outgrowth of
primary cortical neurons. SH2B3 competes for the interaction with TrkA against
SH2B1β, and thus represses NGF□induced signaling activity, including PLCγ,
MEK□ERK1/2 and PI3K□AKT pathways. These data demonstrate that SH2B3, unlike
the other two family members, inhibits neuronal differentiation of PC12 cells and
primary cortical neurons. Taken together, our findings from this thesis imply the
differential requirement of N□cadherin□mediated cell□cell adhesion and SH2B family
proteins during each stages of neuronal differentiation.

中文摘要
在神經分化的過程中，細胞黏著作用和細胞內信息傳遞在每個階段都扮演著
很重要的角色。SH2B蛋白家族是具有多個蛋白模組 (protein domain) 的銜接蛋白
(adaptor protein)，目前已知這些蛋白參與在許多細胞反應當中。在這篇研究報告
中，我們分別發現了SH2B1β和SH2B3的兩個新作用。其中，我們發現在PC12細胞
中過量表現SH2B1β會降低細胞黏著分子N□cadherin的表現量、增加β□catenin第654
號酪胺酸的磷酸化，並且促進神經生長因子 (nerve growth factor, NGF) 所誘導並
的神經軸生長的起始步驟 (neurite initiation)。這項發現說明了N□cadherin造成的
細胞間黏著作用如何影響神經軸生長的起始步驟，並且說明了SH2B1β如何調控
這個過程。
在SH2B蛋白家族中，已知SH2B3在免疫系統發育的過程中，扮演抑制蛋白的
角色。但還不知道SH2B3在神經分化過程中的功能。我們發現在過量表現SH2B3
不僅會抑制神經生長因子誘導的PC12細胞神經分化作用，並且會抑制大腦皮質神
經的神經軸生長。SH2B3會與SH2B1β競爭TrkA的交互作用，藉此抑制NGF引發的
PLCγ，MEK□ERK1/2，以及PI3K□AKT的信息傳遞。此實驗結果說明了SH2B3與另外
兩個蛋白家族成員 (SH2B1, SH2B2) 雖然具有類似的蛋白結構，但反而具有抑制
PC12細胞和大腦皮質神經分化的作用。綜合以上，由此篇論文可推論出在神經分
化的各個階段中，對於N□cadherin形成的細胞間黏著作用和各個SH2B蛋白有不同
的需求性。

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