Cbl and Itch binding sites in ERBB4 CYT-1 and CYT-2 mediate K48- and K63-polyubiquitination, respectively.

ERBB receptors have an important function in mammalian development and normal physiology, but overexpression and poor downregulation of ERBB receptors have been associated with malignant growth. Ligand-induced ERBB receptor signaling is terminated by clathrin-dependent receptor endocytosis, followed by incorporation of activated receptor complexes into multi-vesicular bodies and subsequent degradation in lysosomes. In the case of ERBB1, also known as the EGF receptor, it has been shown that ubiquitination serves as a signal to facilitate internalization and subsequent endosomal sorting, but little is known about the role of ubiquitination of other ERBB receptors.

Recycling of EGFR and ErbB2 is associated with impaired Hrs tyrosine phosphorylation and decreased deubiquitination by AMSH.

ErbB receptors play an important role in normal cellular growth, differentiation and development, but overexpression or poor downregulation can result in enhanced signaling and cancerous growth. ErbB signaling is terminated by clathrin-dependent receptor-mediated endocytosis, followed by incorporation in multi-vesicular bodies and subsequent degradation in lysosomes. In contrast to EGFR, ErbB2 displays poor ligand-induced downregulation and enhanced recycling, but the molecular mechanisms underlying this difference are poorly understood.

Epigenetics: DNA demethylation promotes skeletal myotube maturation.

Mesenchymal progenitor cells can be differentiated in vitro into myotubes that exhibit many characteristic features of primary mammalian skeletal muscle fibers. However, in general, they do not show the functional excitation-contraction coupling or the striated sarcomere arrangement typical of mature myofibers. Epigenetic modifications have been shown to play a key role in regulating the progressional changes in transcription necessary for muscle differentiation.

Role of the C-terminal linear region of EGF-like growth factors in ErbB specificity.

The epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner. Recently, we have shown that the sequence YYDLL in the C-terminal linear region is compatible with binding to all ligand-binding ErbB receptors. In the present study, we show that introduction of the YYDLL sequence into the ErbB1 specific ligands EGF and transforming growth factor-alpha (TGFalpha) broadened their receptor specificity towards ErbB4.

Negative constraints underlie the ErbB specificity of epidermal growth factor-like ligands.

Epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner, but the molecular basis for this specificity is poorly understood. We have previously shown that certain residues in human EGF (Ser(2)-Asp(3)) and TGFalpha (Glu(26)) are not essential for their binding to ErbB1 but prevent binding to ErbB3 and ErbB4. In the present study, we have used a phage display approach to affinity-optimize the C-terminal linear region of EGF-like growth factors for binding to each ErbB receptor and thereby shown that Arg(45) in EGF impairs binding to both ErbB3 and ErbB4.

Ligand depletion negatively controls the mitogenic activity of epidermal growth factor.

EGF activates the ErbB1 receptor, but there appears only a limited correlation between its receptor binding affinity and mitogenic activity. This is indicated by our present observation that in cells with high ErbB1 expression, including SUM102 breast tumor cells, low affinity EGF/Notch chimeras have similarly high mitogenic activity as EGF, in spite of the fact that EGF is superior in inducing receptor tyrosine phosphorylation and p42/p44 MAP-kinase activity. However, as a result of receptor-mediated internalisation high-affinity ligands such as EGF are depleted much more rapidly from the extracellular medium than low-affinity EGF/Notch chimeras.