Identification of Heregulin, a Specific Activator of p185 ^erbB2

TLDR

The erbB2/HER2 proto‑oncogene encodes a 185‑kDa transmembrane tyrosine kinase whose overexpression correlates with poor prognosis in several cancers, and its natural ligands may be the HRG family. Heregulin‑α, a 45‑kDa protein purified from conditioned medium of a human breast tumor cell line, specifically induces phosphorylation of p185 erbB2. Complementary DNA clones of HRG family members were identified, showing similarity to epidermal growth factor family proteins, and recombinant HRG binds a single high‑affinity site (Kd ≈ 10^5 pM) on p185 erbB2, with transcripts present in normal tissues and various cancer cell lines.

Abstract

The proto-oncogene designated erb B2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185 erb B2 ), whose overexpression has been correlated with a poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-α (HRG-α) that specifically induced phosphorylation of p185 erb B2 was purified from the conditioned medium of a human breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all of which are similar to proteins in the epidermal growth factor family. Scatchard analysis of the binding of recombinant HRG to a breast tumor cell line expressing p185 erb B2 showed a single high affinity binding site [dissociation constant ( K d ) = 105 ± 15 picomolar]. Heregulin transcripts were identified in several normal tissues and cancer cell lines. The HRGs may represent the natural ligands for p185 erb B2 .