Multiple positive and negative regulators of signaling by the EGF-receptor
Introduction
The epidermal growth factor (EGF) receptor (EGFR) family of receptor tyrosine kinases (RTKs) is comprised of four members in mammals and one each in Caenorhabditis elegans and Drosophila melanogaster. Signaling by the EGFR family is crucial for the development of mice, fruit flies and nematodes 1, 2, 3, 4, 5. Also, amplification and/or inappropriate activation of EGFR family members is associated with many tumors; moreover, the EGFR has served as a paradigm for the larger family of RTKs, which play similarly important roles in animal development and physiology. Here we discuss some advances published in the past 18 months concerning the factors that positively or negatively regulate signaling mediated by the EGFR. Note that all mechanisms discussed might not act universally as studies from a variety of mammalian cell-types, D. melanogaster and C. elegans have not yet converged (Table 1).
Section snippets
Ligands and dimerization
In mammals, the EGFR family includes ErbB1 (also called EGFR), ErbB2 (also called c-Neu), ErbB3, and ErbB4. As with many other RTKs, EGFR-dependent signal transduction begins with the stabilization of a receptor dimer through ligand binding. In the case of EGFR signaling, however, multiple ligands and the capacity of family members to homodimerize and heterodimerize make this step one of the most complex points of regulation. ErbB ligands include: EGF, transforming growth factor (TGF)α, and
Cellular location and membrane trafficking of EGF receptors
Membrane trafficking events control EGFR signaling — most notably in downregulation but also in other signaling properties [19]. Some EGFR substrates (e.g. Shc, phospholipase Cγ [PLCγ]) are preferentially phosphorylated at the cell surface, whereas others (e.g. EGFR itself, p85 subunit of PI3K) are better phosphorylated by EGFRs associated with endocytic vesicles; furthermore, ErbB2 can promote recycling of ligand-stimulated EGFR [20], adding yet another yet layer of complexity to regulation of
Effectors of EGF receptor signaling
Effector pathways for the EGFR have been defined in several ways: by proteins associated with activated receptors; by proteins phosphorylated by active receptors; by proteins whose activity is regulated by receptor stimulation; and by mutations that result in decreased signaling. Some effectors may well be negative-feedback regulators. The best understood effector pathway is activation of Ras by the recruitment of son-of-sevenless ([SOS] a Ras guanine nucleotide exchange factor [GEF]), to the
Crosstalk
Cells integrate information from distinct signaling pathways; the EGFR is one point of such crosstalk (Figure 2). Mitogenic agonists of G-protein-coupled receptors (GPCRs) stimulate proliferation through ligand-independent activation of the EGFR. These agonists strongly promote EGFR, Shc, and Gab1 tyrosyl phosphorylation, and the activation of MAPK 51, 52. Gβγ subunits and c-src are involved in the activation of the EGFR [53], and EGFR, Pyk2, and c-src appear to be required for maximal MAPK
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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