Biological effects of growth factor receptor interactions: Heterodimerization of epidermal growth factor receptor with wild type or mutant neu receptors.

Format:

Book

Thesis/Dissertation

Author/Creator:

Qian, Xiaolan.

Contributor:

Greene, Mark I., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Cytology.

Molecular biology.

0307.

0379.

Penn dissertations--Biology.

Biology--Penn dissertations.

Local Subjects:

Penn dissertations--Biology.

Biology--Penn dissertations.

0307.

0379.

Physical Description:

181 pages

Contained In:

Dissertation Abstracts International 54-03B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The rat c-neu product is homologous to the Epidermal Growth Factor receptor (EGFr). Slight overexpression of these two receptors leads to cell transformation. In order to explore how these two proto-oncogenic products interact and lead to cell transformation, to examine the requirements for physical interaction, and to define the domains or regions of neu receptor modulating EGFr function, stable cell lines co-expressing EGFr with wild type (wt) or various mutant neu proteins were established and characterized at the biochemical and cellular levels.

EGF induced rapid, reversible heterodimerization of EGFr and p185$\sp{c-neu}$ in transfected cells. The neu ecto-domain was required for inter-receptor association. The truncated neu proteins revealed the preference for heterodimerization over EGFr homodimerization. Co-expression of EGFr with wt p185$\sp{c-neu}$ resulted in elevated tyrosine kinase activity of heterodimeric complex in vivo and in vitro. Together with the associated p185$\sp{c-neu}$, EGFr behaved normally in receptor down-regulation and degradation. An increased EGF binding affinity may be responsible for the synergistic positive biological effects leading to cell transformation. Co-expression of EGFr with kinase deficient mutant neu proteins resulted in less active or inactive heterodimeric complexes. The unproductive mutant heterodimer abolished synergistic transformation, suppressed EGFr response in EGF-dependent transformation, reduced the rate of receptor endocytosis and turnover, diminished DNA synthesis and decreased EGF binding affinity. These results provide the first evidence that heterodimerization with kinase deficient neu proteins displays a dominant negative mutant phenotype and suppresses EGFr functions. Co-expression of EGFr with truncated kinase active neu proteins did not change the cell phenotype. The deletion of neu ecto-domain limited their ability to interact with EGFr. The heterodimerization of EGFr with carboxyl terminal region deleted neu receptor could not enhance cell transformation.

The results confirm that only the intact kinase active neu can physically and functionally interact with EGFr leading to synergistic transformation. These studies indicated the role of heterodimerization of EGFr and neu/c-erbB2 in the mechanism of underlying inter-receptor activation and synergistic signaling that may be responsible for the transition from normal receptor function into oncogenesis.

Notes:

Thesis (Ph.D. in Biology) -- Graduate School of Arts and Sciences, University of Pennsylvania, 1993.

Source: Dissertation Abstracts International, Volume: 54-03, Section: B, page: 1198.

Supervisor: Mark I. Greene.

Local Notes:

School code: 0175.

Access Restriction:

Restricted for use by site license.