A 1.8 kb alternative transcript from the human epidermal growth factor receptor gene encodes a truncated form of the receptor

Abstract

The epidermal growth factor receptor (EGFR) is encoded by the c-erbB1 proto-oncogene and plays an important role in the control of cell growth and differentiation. To study the potential growth regulatory role of soluble EGF receptors, we have isolated cDNA clones encoding a truncated, secreted form of the human EGFR. The 5' sequence of this cDNA is identical to the EGFR transcript encoding the full-length receptor through exon 10. The unique 3' sequence encodes two additional amino acid residues before encountering an in-frame stop codon, a poly(A) addition site and a poly(A)+ tail. Sequence comparison with genomic DNA sequences demonstrates that this alternative transcript arises by read-through of a splice donor site. As a result, this transcript encodes a portion of the extracellular ligand-binding domain, but lacks the transmembrane domain and the intracellular tyrosine kinase catalytic domain present in the EGFR. Conditioned medium from transfected fibroblast cells contains a 60 kDa protein that is specifically immunoprecipitated by an EGFR monoclonal antibody. These findings demonstrate that alternative processing of the human EGFR transcript produces a secreted product composed of only the extracellular ligand-binding domain.

Isolation and characterization of four alternate c-erbB3 transcripts expressed in ovarian carcinoma-derived cell lines and normal human tissues

“…The exon-intron boundaries determined from the analysis of cDNA clones encoding alternate c-erbB1 transcripts (Reiter and Maihle, 1996) are consistent with the genomic structure of the avian c-erbB1 gene (Callaghan et al, 1993). The truncated c-erbB2 transcript also shares the same exon-intron boundary at the 3' end of exon 15 with avian c-erbB1.…”

“…In contrast, a truncated form of the rat ErbB-1 is generated by alternative splicing (Petch et al, 1990). Interestingly, recent studies on the human c-erbB1 gene suggest that both alternative splicing (Reiter and Maihle, in preparation) and alternative processing (Reiter and Maihle, 1996) mechanisms are used to generate soluble forms of this receptor. In contrast, soluble forms of ErbB-2 and the ErbB-4 can also be generated by proteolytic cleavage of the full-length receptors (Zabrecky et al, 1991;Vecchi et al, 1996), although one truncated form of ErbB-2 is also generated by translation of an alternate transcript (Scott et al, 1993).…”

The Membrane Form of the Type II IL-1 Receptor Accounts for Inhibitory Function

“…This was achieved by replacing the putative cleavage region in IL-1RII (i.e., the 20-residue stalk sequence VVHNTLS FQTLRTTVKEASS between the the end of the third Ig-like loop and the beginning of the transmembrane region) with the corresponding region of the EGFR, a membrane protein insensitive to protease cleaving and whose soluble form is generated by alternative splicing (41). Although the exact sequence motif recognized by the cleaving protease in IL-1RII is not known, the molecular mass of sIL-1RII (about 60 kDa), structural data, and the presence of three Ig-like loops in the soluble receptor all indicate that the target site for the cleaving metalloproteinase is confined to the stalk region of the receptor molecule (11, 18 -24).…”

Sequences Adjacent to the 5′ Splice Site Control U1A Binding Upstream of the IgM Heavy Chain Secretory Poly(A) Site

“…2 These are predominantly receptors but also represented are transcription factors and biologically important enzymes. For instance, the oncogenes epidermal growth factor receptor and HER2 receptor are both receptors with truncated forms (38,39). In both cases the truncated versions are festooned with novel U1A binding motifs that may play a role in silencing the truncated forms.…”