The Relationship between Human Epidermal Growth-like Factor Receptor Expression and Cellular Transformation in NIH3T3 Cells

Abstract

A collection of cell lines expressing each human epidermal growth factor receptor (HER) family member alone or in all pairwise combinations in a clone of NIH3T3 cells (3T3-7d) devoid of detectable epidermal growth factor receptor family members has been generated. Transformation, as measured by growth in soft agar, occurred only in the presence of appropriate ligand and only in cells expressing two different HER family members. Transfection of oncogenic neu (Tneu), conferred ligand-independent transformation only in cells which co-expressed HER1, HER3, or HER4, but not when expressed alone or with HER2. Cell lines were also tested for their ability to form tumors in animals. None of the cell lines expressing single HER family members was able to form tumors in animals with the exception of HER1, which was weakly tumorigenic. Although unable to form tumors when expressed alone, HER2 was tumorigenic when expressed with HER1 or HER3, but not HER4. Of all complexes analyzed, cells expressing HER1 ؉ HER2 were the most aggressive. The relationship between HER1 activation, intracellular calcium fluxes, and phospholipase C␥1 activation is well established. We found that activation of HER1 was required for the induction of a calcium flux and the phosphorylation of phospholipase C␥1. These activities were independent of, and unaffected by, the co-expression of any other family member. Further, heregulin stimulation of all cell lines including those containing HER1 did not demonstrate any effect on intracellular calcium levels or phospholipase C␥1 phosphorylation. This demonstrates that heregulin induced cellular transformation by activating HER3-and HER4-containing complexes does not require the activation of either phospholipase C␥1 or the mobilization of intracellular calcium.

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

“…Moreover, although unable to form tumours when expressed alone, HER2 was tumorigenic when expressed with HER1 or HER3, but not HER4. Of all combinations analysed, cells expressing both HER1 and HER2 were the most aggressive (Cohen et al, 1996). In addition, when HER2-expressing cells were transfected with HER4, antiproliferative and differentiation responses were observed (Sartor et al, 2001), suggesting that HER4 signalling has an opposite effect than HER2 signalling.…”

Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

“…However, ErbB-4 expressing cells (D4), exhibited a modest dose-dependent mitogenic response in comparison to its counterpart NRG-1b control. Because di erent heterodimeric complexes of ErbB proteins can diversify and enhance signaling by EGF-like ligands (Cohen et al, 1996;Pinkas-Kramarski et al, 1996;Riese et al, 1995), cells co-expressing two ErbB proteins (for example D12 cells co-express ErbB-1 and ErbB-2) were also tested for NRG-4-induced mitogenicity. Of the tested combinations, namely: D12, D13, D23 and D24 cells, a cell line expressing a combination of ErbB-4 with ErbB-2 (D24 cells) was the only line that responded mitogenically to the novel peptide ( Figure 3a).…”

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

“…Unlike ErbB-3 homodimers, that are functionally inactive (Riese et al, 1995;Pinkas-Kramarski et al, 1996b), ErbB-2/ErbB-3 heterodimers appear to be the predominant receptor of NDF in carcinoma cells . Consistent with the high stability and potent proliferative action of this complex, coexpression of ErbB-2 and ErbB-3 confers a transformed phenotype (Alimandi et al, 1995;Wallasch et al, 1995), whose potency in ®broblasts is second only to an ErbB-1/ErbB-2 heterodimer (Cohen et al, 1996;Zhang et al, 1996).…”