ErbB receptors direct

Holbro T, Hynes NE. ErbB receptors directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004 44 195-217. 

In addition to the approaches covered in a recent review [20], the first comprehensive model covering receptor dimerization and internalization has been recently described [21], In this work, the authors use direct time-dependent measurement of the phosphorylation of the four ErbB receptor species, as well as protein quantitation to develop a comprehensive mechanistic model of receptor dimerization and internalization. Once this comprehensive, quantitative framework was developed, the authors were able to show that receptor dephosphorylation, a key step in the downregulation of ErbB-driven signaling, was restricted to intracellular compartments. 

Trastuzumab is a monoclonal antibody directed against the HER-2/neu receptor. HER-2/neu is a member of the erbB (or HER) growth factor receptor family and is expressed at low levels in the epithelial cells of normal breast tissue. The overexpression of HER-2/neu is associated with increased transmission... 

Both mature and nascent forms of ErbB-2 are sensitive to geldanamycin. The drug seems to prevent exit of nascent ErbB-2 from the endoplasmic reticulum (Chavany et al. 1996), and directs the precursor to degradation by the proteasome (Mimnaugh et al. 1996). Sensitivity of ErbB-2 is conferred by the kinase domain of the receptor, but the functionality of the kinase is not necessary, as a kinase-defective mutant of ErbB-2 is also sensitive to geldanamycin (Xu et al. 2001). ErbB-2 is subject to a complex form of degradation, involving the sequential activity of a caspase family protease that cleaves the carboxyl-terminal tail of the receptor from the rest of the molecule (Tikhomirov and Carpenter 2000 Tikhomirov and Carpenter 2001). The cytoplasmic part is ubiquitinated and is subjected to... 

As in the case of other receptor tyrosine kinases like erbB 1 and erbB2, efforts have been directed to identify and develop hiunanized antibodies that block the physical interaction between IGF-IR and its cognate ligands. Although obtained by applying different approaches, these antibodies have been shown in a variety of preclinical systems to specifically bind to the extracellular domain of IGF-IR, preventing downstream signahng. 

Signaling by ErbB-3 and ErbB-4 inflicts an additional level of complexity by applying a wide but shared variety of direct ligands to both receptors. Genetic evidence implies that signaling by neuregulins is essential for epithelial organs, for effectors of the nervous system such as Schwann cells and neu-... 

TRASTUZUMAB Trastuzumab (herceptin) targets the HER2/neu (ErbB-2) member of the EGE family of protein tyrosine kinase receptors. Activation of HER2/neu enhances metastatic potential and inhibits apoptosis. HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. Trastuzumab can initiate Fcy-receptor-mediated ADCC and directly induce apoptosis. 

Fry, D.W. Site-directed irreversible inhibitors of the erbB family of receptor tyrosine kinases as novel chemotherapeutic agents for cancer. Anticancer Drug Des., 15, 3-16 (2000)... 

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