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ErbB signaling pathway

ErbB signaling pathway

ErbB(红细胞原癌基因B)属于表皮生长因子受体家族,包括一个细胞外区域、跨膜区域和细胞质酪氨酸激酶区域。在人类中,ErbB家族包括四个成员:ErbB1(Her1),ErbB2(Her2),ErbB3(Her3),ErbB4(Her4)。
 
ErbB1也被称为EGFR(表皮生长因子受体)。通常情况下,EGFR表达在上皮细胞的表面。但在某些肿瘤细胞中,它常常过度表达。EGFR的过度表达与肿瘤细胞的转移、侵入和预后不良相关。EGFR通过与EGFTGF-α(转化生长因子α)结合被激活。激活的EGFR从一个无活性的单体转变为一个活性的同源二聚体。
 
ErbB2没有已知的配体。但ErbB2是与其他三个受体形成异二聚体的最佳候选者。研究发现,ErbB2的扩增或过度表达与某些乳腺癌的发展和进展有关。ErbB2最近已成为某些特定乳腺癌的重要生物标志物和治疗靶点。
 
ErbB3在正常成人人体的神经系统、皮肤、泌尿系统和生殖系统中经常出现。它可以与神经再生因子1(NRG1)或NRG2结合。由于缺乏激酶区域,ErbB3需要与其他三个家族成员结合形成活性异二聚体。而ErbB3更倾向于与ErbB2结合。
 
ErbB4有许多配体,如NRG1、NRG2、NRG3NRG4、表皮再生素、HB-EGF和胰岛素样生长因子。ErbB4突变在许多癌症中被检测到。
 
ErbB信号通路是指通过与多种信号转导分子结合使ErbB成员发生二聚化或异二聚化的多个过程,并促进自磷酸化和下游信号级联。
 
ErbB信号通路的功能
ErbB信号通路通过介导PI3K/Akt信号通路JAK/STAT信号通路MAPK信号通路调节细胞增殖、迁移、分化、凋亡和细胞运动能力。
 
ErbB家族成员及其一些配体在许多形式的癌症中经常过度表达、扩增或突变,使它们成为重要的治疗靶点。
 
ErbB信号通路的过程
在四个ErbB受体中,ErbB1和ErbB4是常被研究的。
 
当EGF或TGF-α结合时,EGFR会形成具有活性的同源二聚体。EGFR二聚化刺激其胞内蛋白酪氨酸激酶活性,磷酸化酪氨酸残基。这些磷酸化的残基提供了具有SH2(Src同源2)或PTB(磷酸酪氨酸结合区)结构域的蛋白信号分子的停靠位点。激活的受体复合物中的蛋白质相互作用刺激ras蛋白,导致磷酸化级联反应的发展和丝裂原活化蛋白激酶(MAPK)的激活,从而激活磷脂酰肌醇激酶3(PI3K)-Akt、MPAK和JNK信号通路。这些信号通路进一步触发基因转录,促进DNA合成和细胞增殖。
 
NRG1与ErbB4具有高亲和力。NRG1直接结合到ErbB3或ErbB4,诱导后者的同源或异源二聚化。二聚化激活酪氨酸激酶活性。一旦ErbB受体被激活,ErbB2结合到ErbB4上促进酪氨酸自体磷酸化。此过程随后触发下游磷酸化级联反应和相关信号通路的发生。ErbB传递的信号引发了广泛的生物功能,包括心脏发育、突触形成以及Schwann细胞的增殖和分化。研究表明,通过P13K-Akt信号通路,NRG1参与了寡突胶质细胞的发育与分化以及Schwann细胞的增殖。
 

What Is ErbB?

ErbB (erythroblastic oncogene B) belongs to the epidermal growth factor receptor family and consists of an extracellular domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. In humans, the ErbB family includes four members: ErbB1 (Her1), ErbB2 (Her2), ErbB3 (Her3), ErbB4 (Her4).

ErbB1 is also called EGFR (epidermal growth factor receptor). Normally, EGFR is expressed on the surface of epithelial cells. But it is often overexpressed in some tumor cells. The overexpression of EGFR is associated with metastasis, invasion and poor prognosis of tumor cells. EGFR is activated by binding to EGF or TGF-α (transforming growth factor α). Activated EGFR is converted from an inactive monomer to an active homodimer.

ErbB2 does not have a known ligand. But ErbB2 is the best candidate for the formation of a heterodimer with the other three receptors. Studies have revealed that amplification or overexpression of ErbB2 is associated with the development and progression of some breast cancers. ErbB2 has recently become an important biomaker and therapeutic target of some certain breast cancers.

ErbB3 is often seen in the nervous system, skin, urinary tract, and reproductive system of normal adult human. can bind to neuregulin 1 (NRG1) or NRG2. Due to lack of the kinase domain, ErbB3 needs to bind to the other three family members form an active heterodimer. And ErbB3 prefers the binding with ErbB2.

ErbB4 has many ligands such as NRG1, NRG2,  NRG3, NRG4, epiregulin, HB-EGF, and betacellulin. ErbB4 mutation is detected in many cancers.

What Is ErbB Signaling Pathway?

The ErbB signaling pathway refers to multiple processes by which ErbB members dimerize or heterodimerize through the binding with numerous signal transducers to promote the autophosphorylation and subsequent downstream signaling cascades.

The Function of ErbB Signaling Pathway

The ErbB signaling regulates cell proliferation, migration, differentiation, apoptosis, and cell motility by mediating the PI3K/Akt pathway, the JAK/STAT pathway, and the MAPK signaling pathway.

ErbB family members and some of their ligands are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets.

The Process of ErbB Signaling Pathway

Among the four ErbB receptors, ErbB1 and ErbB4 are popular to be studied.

Upon binding to EGF or TGF-α, EGFR is dimerized to a homodimer with activity. EGFR dimerization stimulates its intracellular protein-tyrosine kinase activity, which phosphorylates the Tyr residues. These phosphorylated residues provide docking sites for the protein signaling molecules with an SH2 (Src homology 2) or a PTB domain. Protein interactions in activated receptor complexes stimulate ras proteins, leading to the development of a phosphorylation cascade and activation of mitogen-activated protein kinase (MAPK), thereby activating phosphatidylinositol kinase-3 (PI3K) -Akt, MPAK, and JNK signaling pathways. These signaling pathways further trigger gene transcription, which promotes DNA synthesis and cell proliferation.

NRG1 has a high affinity with ErbB4. NRG1 directly binds to ErbB3 or ErbB4, which induces homologous or allogenic dimerization of the latter. The dimerization activates tyrosine kinase activity. Once the ErbB receptors are activated, ErbB2 binds to ErbB4 to facilitate tyrosine autophosphorylation. This process subsequently triggers the occurrence of downstream phosphorylation cascades and related signaling pathways. Signals transmitted by ErbB induce a wide range of biological functions, including cardiac development, synaptic formation, and proliferation and differentiation of Schwann cells. Studies have shown that NRG1 is involved in the development &differentiation of oligodendrocytes and the proliferation of Schwann cells through the P13K-Akt pathway.