The International Journal of Biochemistry & Cell Biology
Molecules in focusEGF receptor
Introduction
Cell surface molecules communicate information from the external milieu to the cell. This sensing is critical in multicellular organisms as the cells must function appropriately to their localization and respond in concert to the needs of the organism. One major family of sensors is comprised of transmembrane receptors with intrinsic protein tyrosine kinase activity (RPTK), the prototypal member of which is the EGF receptor (EGFR; also referred to as HER (human EGF receptor) and c-erbB1) as it was the first receptor described to possess tyrosine kinase activity and the first member of this superfamily to be sequenced. Co-incidentally, the structure of EGFR appears to represent an archetypal pattern for this superfamily of extracellular sensors that control basic cell functions. These receptors all present kinase activity directed against tyrosine residues located both within the receptor itself (autophosphorylation) and on target downstream molecules. Ligand binding activates the kinase which, with a possible few minor exceptions, is required for all cellular responses. The pleiotropic cell responses, actuated via still ill-defined pathways, include cell proliferation, migration, and differentiation as well as homeostatic functioning.
Section snippets
Structure
EGFR is somewhat unusual among RPTK in that there is a single isoform, from a single 26 exon gene located across 110kb on chromosome 7p11–13, which serves as the sole or overwhelmingly predominant receptor for multiple distinct ligands including EGF, TGFα, amphiregulin, HB-EGF and a number of virally-encoded factors. The protein product of this gene is most often an 1186 amino acid mature transmembrane glycoprotein (Fig. 1). An amino-terminal 622 amino acid extracellular domain containing two
Expression and degradation
EGFR is present on all epithelial and stromal cells as well as select glial and smooth muscle cells. It is transcribed from a TATA-less promoter as two predominant large mRNA species that differ by the extent of 3′ untranslated sequence (in humans as ∼6 kb and ∼9 kb species). Relatively little has been reported about transcriptional control of EGFR, though it appears to decline with cellular aging at least in dermal fibroblasts. Post-translational processing and trafficking has been extensively
Biological function
EGFR is a pleiotropic signaler. The integrated biological response to EGFR activation varies from mitogenesis to apoptosis, migration to differentiation to dedifferentiation even in the same cell depending on the context, which includes cell density, type of matrix, other cytokines, and even the position within a cell colony. The molecular bases of these responses is only now being defined [6].
EGFR kinase triggers numerous downstream signaling pathways similar to other RPTK and tyrosine
Medical/industrial application
Control of EGFR signaling will likely provide important opportunities in three main areas—cancer treatment, organ repair, and cell production. EGFR is the receptor most often found upregulated in a wide variety of human tumors [13]. Due to its early identification as the proto-oncogene of the transforming v-erbB oncogene and its association with the genesis of numerous tumors, EGFR has been the target of numerous therapies, ranging from therapeutic and imaging antibodies to toxin-linked ligands
Acknowledgements
Supported by grants from the National Institute of General Medical Sciences (NIH), National Cancer Institute (NIH), Veterans Administration, and the Bioengineering Division of the National Science Foundation. Angela Glading, Jareer Kassis, Jose Souto, and Philip Chang provided important criticism for this review.
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I apologize to all authors whose important works contributed to our understanding of the EGF receptor but could not be directly cited in this review due to the limitations in references.