EGF与细胞信号传导 Signal Transduction 涂 桂 洪guihong.tu@watsin.com.cn
Contents EGF与EGF受体 EGF信号传导机制 EGF受体分布 EGF受体过度表达与肿瘤 其他
科学研究发现：EGF是皮肤更新所需的关键基础物质。
细胞周期 细胞核和细胞质分成两半 分裂前的静止期 RNA 和蛋白合成，仿垂体形成 关键调节点 细胞或停留在G0期，或进入有序死亡，除非有特别的刺激源 静止期 RNA和蛋白合成，细胞可从这个时期进入G0期 合成期 DNA复制
EGF与EGFR组成一个信号传导系统
What is EGF?
EGF gene located in the human chromosome No.4
The primary structure of EGF EGF, Epidermal Growth Factor, is a small peptide with 53 amino acids, occurred widely in the mammalian. At least 10 members in EGF-like family
Three dimensional structure of EGF Disulfide bonds EGF is the most stable polypeptide of all proteins found up to now. No decrease of activity was found in 100℃ of water for 30 minutes.
The refined structure & function of EGF molecule His2, Phe3; ErbB-2/ErbB-3 activator receptor binding activity Leu 15 ; ligand-receptor complex 20-31 receptor-binding site antigenic determinant Tyr13 Cys 47 high affinity to receptor The refined structure & function of EGF molecule stimulating cell proliferation
EGF受体（EGFR）
The EGFR (ErbB) family and ligands TGFa Amphiregulin b-cellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin Heregulins Cysteine-rich domains 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase domain C-terminus ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4
I a ligand binds to its extracellular domain II receptor dimerization III activation of tyrosine kinase activity IV tyrosine autophosphorylation V leading to mitogenic signaling and other cellular activities EGFR signal transduction
The first step, EGF binds to the extracellular domain of the EGF receptor (EGFR) The second step, two EGF-EGFR dimers come together The third step, EGF-EGFR dimer complex binds a molecule of ATP
Induce a series of complex biochemical reactions in the cell The fourth step, ATP-bound dimer complex interacts with another (EGF-EGFR) dimer complex. The finally, Grb2-Sos1 complex recognizes the phosphorylated EGFR and binds Induce a series of complex biochemical reactions in the cell
The final fate of EGF and it’s receptor
EGFR在各种正常组织中的分布
Conclusion *EGF是一个信号分子，EGF的作用是通过与其受体EGFR结合，形成细胞信号传导系统, 是细胞分裂、增殖与分化的原动力 *一个EGF分子只对一个细胞作用一次，因此不可能出现组织过度增生的问题 *EGFR广泛分布于各种组织，理论上说EGF对这些组织的损伤修复都可能有作用 * EGF必须接触到靶细胞和靶组织才能起作用
EGFR与肿瘤发生 1 EGFR在肿瘤细胞中过度表达 2 EGFR基因发生重排和突变 3 这种过度表达和突变不是由EGF引起的
肿瘤细胞存在的4种不同EGF受体
EGFvIII variant EGFRvIII expression is detected in 52-67% of primary human glioblastoma tumors, also in various human cancers, including breast, prostate, ovarian, lung, and medulloblastoma tumors , but has not been detected in normal adult tissue EGFRvIII expression significantly enhanced tumorigenicity of MCF-7 cells in athymic nude mice with P < 0.001 EGFvIII is constitutively phosphorylated at the C-terminal tyrosine residues although it is incapable of binding EGF or transforming growth factor (TGF)
Endocrine-Related Cancer (2001) 8 161–173 4个药物被FDA批准临床的药物
Endocrine-Related Cancer (2003) 10 1–21 9个被FDA批准临床的药物
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