Boster Pathways-> Kinase Signaling


ErbB/HER Signaling Pathway


The ErbB signaling pathway encompasses a variety of processes in which ErbB members dimerize or heterodimerize via binding to a diverse array of signal transducers, thereby promoting autophosphorylation and subsequent downstream signaling cascades.

What is ERBB?

ErbB (erythroblastic oncogene B) is a member of the epidermal growth factor receptor family. It is composed of three domains: an extracellular domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The ErbB family in humans consists of four members: ErbB1 (Her1), ErbB2 (Her2), ErbB3 (Her3), and ErbB4 (Her4) (Her4).

ErbB1 is also known as EGFR (epidermal growth factor receptor). EGFR is normally expressed on the epithelial cell surface. However, it is frequently overexpressed in certain tumor cells. Overexpression of EGFR is associated with tumor cell metastasis, invasion, and poor prognosis. By binding to EGF or TGF- (transforming growth factor ), the EGFR is activated. The inactive monomer of activated EGFR is converted to an active homodimer.

ErbB2 is not known to have a ligand. However, ErbB2 is the best candidate for heterodimerization with the other three receptors. Amplification or overexpression of ErbB2 has been linked to the development and progression of certain types of breast cancer. ErbB2 has recently emerged as a critical biomaker and therapeutic target in certain types of breast cancer.

ErbB3 is frequently detected in the nervous system, skin, urinary tract, and reproductive system of healthy adults. can interact with neuregulin 1 (NRG1) or neuregulin 2 (NRG2). Due to the absence of a kinase domain, ErbB3 must form an active heterodimer with the other three family members. Furthermore, ErbB3 prefers to interact with ErbB2.

Numerous ligands for ErbB4 exist, including NRG1, NRG2, NRG3, NRG4, epiregulin, HB-EGF, and betacellulin. Numerous cancers have been identified with an ErbB4 mutation.

ErbB Signaling Pathway

The ErbB signaling pathway encompasses a variety of processes in which ErbB members dimerize or heterodimerize via binding to a variety of signal transducers, thereby promoting autophosphorylation and subsequent downstream signaling cascades.

ErbB/HER Signaling

The ErbB receptor tyrosine kinase family consists of four cell membrane receptors that are activated upon ligand binding and dimerization of the receptor. Dimerization is a critical step in ErbB family signaling, and ErbB receptors can either homodimerize or heterodimerize with other family members, allowing for multiple receptor combinations. The ErbB receptors regulate cellular processes such as proliferation, differentiation, apoptosis, migration, and motility via a variety of signaling pathways, including the Akt and MAPK pathways. Along with their functions on the cell surface, ErbB family proteins are found in the nucleus, where they function as kinases and transcriptional regulators. Inadequate ErbB signaling has been linked to the onset of neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. Additionally, several types of cancer, including lung, breast, stomach, colorectal, head and neck, and pancreatic cancers, are associated with mutations or increased expression of members of the ErbB family. Due to the critical role of ErbB family members in the development and malignancy of these tumors, they have been significant therapeutic targets.

Regrettably, cancers treated with currently available targeted therapies eventually develop resistance to them. Thus, the role of targeted drug combinations or targeted drug combinations with cytotoxic therapies, rather than single therapeutics, is currently being investigated.

Function of ErbB Signaling Pathway

Functions

By mediating the PI3K/Akt, JAK/STAT, and MAPK signaling pathways, ErbB signaling regulates cell proliferation, migration, differentiation, apoptosis, and motility. Members of the ErbB family and several of their ligands are frequently overexpressed, amplified, or mutated in a variety of types of cancer, making them attractive therapeutic targets.

Apart from their roles as receptors on the cell surface, ErbB family proteins are also found in the nucleus, where they act as kinases and transcriptional regulators. For instance, EGFR may be transported into the nucleus and act as a tyrosine kinase, phosphorylating and stabilizing PCNA. Similarly, ErbB2 bound to the membrane interacts with importin 1 and Nup358 and migrates to the nucleus via endocytic vesicles. ErbB2 regulates the transcription of a number of downstream genes, including COX-2, within the nucleus.

Additionally, stimulation with NRG or TPA induces ErbB4 cleavage by -secretase, resulting in the release of an 80 kDa intracellular domain that translocates to the nucleus to induce differentiation or apoptosis. ErbB4 can also form a complex with TAB2 and N-CoR to repress gene expression following activation and cleavage.

mechanism of ErbB Signaling

Mechanism

Upon binding to EGF or TGF-, EGFR dimerizes to a functional homodimer. Dimerization of EGFR activates its intracellular protein-tyrosine kinase activity, phosphorylating Tyr residues. These phosphorylated residues serve as docking sites for signaling proteins that contain an SH2 (Src homology 2) or a PTB domain. Protein interactions within activated receptor complexes stimulate ras proteins, resulting in the formation of a phosphorylation cascade and activation of mitogen-activated protein kinase (MAPK), thereby activating the phosphatidylinositol kinase-3 (PI3K)-Akt, MPAK, and JNK signaling pathways. Additionally, these signaling pathways promote gene transcription, which results in increased DNA synthesis and cell proliferation.

NRG1 exhibits a strong affinity for ErbB4. NRG1 binds directly to ErbB3 or ErbB4 and induces the latter's homologous or allogenic dimerization. Tyrosine kinase activity is activated by dimerization. After activation of the ErbB receptors, ErbB2 binds to ErbB4 and facilitates tyrosine autophosphorylation.

This process then initiates downstream phosphorylation cascades and signaling pathways. ErbB signals regulate a variety of biological functions, including cardiac development, synaptic formation, and Schwann cell proliferation and differentiation. NRG1 has been implicated in the development and differentiation of oligodendrocytes, as well as the proliferation of Schwann cells, via the P13K-Akt pathway.