Biomedical subjects

E Penuel

Publications and source records attributed to E Penuel.

3 recordsLinked to original sources

PubMed2001

Structural requirements for ErbB2 transactivation.

ErbB2 is a unique member of the ErbB family of receptor tyrosine kinases that is distinguished by the fact that no ligand has yet been identified. Due to the absence of an ErbB2 ligand, alternative mechanisms are used for ErbB2 activation. As such, when ErbB2 is overexpressed, kinase activation occurs in the absence of ligand because of constitutive homodimerization. However, at normal expression levels ErbB2 acts as the shared coreceptor for the ErbB family, and these heterodimeric complexes are activated in response to the partner ligand. While the extracellular domain and transmembrane domains are necessary for ErbB2 transactivation, the carboxy terminus is also required. Specifically, ligand-dependent ErbB2 transactivation requires a discrete three-amino-acid segment, located at the C-terminus of ErbB family members ErbB3, ErbB4, and the epidermal growth factor receptor. Transactivation of ErbB2 via the three-amino-acid segment likely represents a conserved mechanism for regulated signaling by the ErbB family of receptors.

Amino Acid Sequence↗

PubMed1999

The biology of human epidermal growth factor receptor 2.

Our understanding of the normal signaling mechanisms and functions of human epidermal growth factor receptor 2 (HER2) and other members of the HER family, namely epidermal growth factor receptor, HER3, and HER4, is growing rapidly. Activation of these receptors results in a diverse array of signals through the formation of homodimeric and heterodimeric receptor complexes; HER2 is the preferred dimerization partner for the other HERs. These oligomeric receptor complexes activate distinct signaling pathways, such as the Ras-MAPK and PI3-kinase pathways. These, in turn, affect various cellular processes. Recent gene deletion experiments in mice point to an important role for HER2 in cardiac and neural development, and evidence from other studies indicates that HER2 is involved in normal breast growth and development. Thus, HER2 is a key component of a complex signaling network that plays a critical role in the regulation of tissue development, growth, and differentiation.

Animals↗

PubMed1999

Transformation by v-Src: Ras-MAPK and PI3K-mTOR mediate parallel pathways.

An increase in the level of active, GTP-bound Ras is not necessary for transformation of chicken embryo fibroblasts (CEF) by v-Src. This suggests that other Ras-independent pathways contribute to transformation by v-Src. To address the possibility that activation of phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR/FRAP), represents one of these pathways, we have examined the effect of simultaneous inhibition of the Ras-MAPK and PI3K-mTOR pathways on transformation of CEF by v-Src. Transformation was assessed by the standard parameters of morphological alteration, increased hexose uptake, loss of density inhibition, and anchorage-independent growth. Inhibition of the Ras-MAPK pathway by expression of the dominant-negative Ras mutant HRasN17 or by addition of the MAPK kinase (MEK) inhibitor PD98059 reduced several of these parameters but failed to block transformation. Similarly, inhibition of the PI3K-mTOR pathway by addition of the PI3K inhibitor 2-[4-morpholinyl]-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the mTOR inhibitor rapamycin, although reducing several parameters of transformation, also failed to block transformation. However, simultaneous inhibition of signaling by the Ras-MAPK pathway and the PI3K-mTOR pathway essentially blocked transformation. These data indicate that transformation of CEF by v-Src is mediated by two parallel pathways, the Ras-MAPK pathway and the PI-3K-mTOR pathway, which both contribute to transformation. The possibility that simultaneous activation of other pathways is also required is not excluded.

Animals↗