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ErbB signaling pathway

ErbB signaling pathway

ErbB(紅細胞原癌基因B)屬于表皮生長因子受體家族,包括一個細胞外區域、跨膜區域和細胞質酪氨酸激酶區域。在人類中,ErbB家族包括四個成員:ErbB1(Her1),ErbB2(Her2),ErbB3(Her3),ErbB4(Her4)。
 
ErbB1也被稱為EGFR(表皮生長因子受體)。通常情況下,EGFR表達在上皮細胞的表面。但在某些腫瘤細胞中,它常常過度表達。EGFR的過度表達與腫瘤細胞的轉移、侵入和預后不良相關。EGFR通過與EGFTGF-α(轉化生長因子α)結合被激活。激活的EGFR從一個無活性的單體轉變為一個活性的同源二聚體。
 
ErbB2沒有已知的配體。但ErbB2是與其他三個受體形成異二聚體的最佳候選者。研究發現,ErbB2的擴增或過度表達與某些乳腺癌的發展和進展有關。ErbB2最近已成為某些特定乳腺癌的重要生物標志物和治療靶點。
 
ErbB3在正常成人人體的神經系統、皮膚、泌尿系統和生殖系統中經常出現。它可以與神經再生因子1(NRG1)或NRG2結合。由于缺乏激酶區域,ErbB3需要與其他三個家族成員結合形成活性異二聚體。而ErbB3更傾向于與ErbB2結合。
 
ErbB4有許多配體,如NRG1、NRG2、NRG3NRG4、表皮再生素、HB-EGF和胰島素樣生長因子。ErbB4突變在許多癌癥中被檢測到。
 
ErbB信號通路是指通過與多種信號轉導分子結合使ErbB成員發生二聚化或異二聚化的多個過程,并促進自磷酸化和下游信號級聯。
 
ErbB信號通路的功能
ErbB信號通路通過介導PI3K/Akt信號通路JAK/STAT信號通路MAPK信號通路調節細胞增殖、遷移、分化、凋亡和細胞運動能力。
 
ErbB家族成員及其一些配體在許多形式的癌癥中經常過度表達、擴增或突變,使它們成為重要的治療靶點。
 
ErbB信號通路的過程
在四個ErbB受體中,ErbB1和ErbB4是常被研究的。
 
當EGF或TGF-α結合時,EGFR會形成具有活性的同源二聚體。EGFR二聚化刺激其胞內蛋白酪氨酸激酶活性,磷酸化酪氨酸殘基。這些磷酸化的殘基提供了具有SH2(Src同源2)或PTB(磷酸酪氨酸結合區)結構域的蛋白信號分子的停靠位點。激活的受體復合物中的蛋白質相互作用刺激ras蛋白,導致磷酸化級聯反應的發展和絲裂原活化蛋白激酶(MAPK)的激活,從而激活磷脂酰肌醇激酶3(PI3K)-Akt、MPAK和JNK信號通路。這些信號通路進一步觸發基因轉錄,促進DNA合成和細胞增殖。
 
NRG1與ErbB4具有高親和力。NRG1直接結合到ErbB3或ErbB4,誘導后者的同源或異源二聚化。二聚化激活酪氨酸激酶活性。一旦ErbB受體被激活,ErbB2結合到ErbB4上促進酪氨酸自體磷酸化。此過程隨后觸發下游磷酸化級聯反應和相關信號通路的發生。ErbB傳遞的信號引發了廣泛的生物功能,包括心臟發育、突觸形成以及Schwann細胞的增殖和分化。研究表明,通過P13K-Akt信號通路,NRG1參與了寡突膠質細胞的發育與分化以及Schwann細胞的增殖。
 

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.



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