Proteolytic processing of TGFα redirects its mitogenic activity: The membrane-anchored form is autocrine, the secreted form is paracrine

Meejeon Roh, Andrew J. Paterson, Kan Liu, Joanne McAndrew, Edward Chin, Jeffrey E. Kudlow

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Wild-type transforming growth factor α (TGFα) expression in lactotrope cells in the pituitary gland led to lactotrope-specific pituitary hyperplasia and adenomata. To indicate whether the EGF receptor is involved in this TGFα-mediated phenotype, we bred TGFα mice with mice expressing the cytoplasmic truncated-EGF receptor (EGFR-tr), which is dominant-negative in other models. These bitransgenic mice developed pituitary pathology despite expression of the dominant-negative receptor. To further characterize this observation, we generated two lineages of transgenic mice that overexpress mutant forms of TGFα: a processed soluble form (s TGFα) and a cytoplasmic-deleted form (TGFαΔC). While sTGFα expression in lactotrope cells failed to induce autocrine lactotrope hyperplasia, the pituitary became very enlarged due to proliferation of neighboring interstitial cells. In contrast, the TGFαΔC mice did not develop a phenotype, although the mRNA and protein were present in the pituitary and this form of TGFα was confirmed to be biologically active and targeted properly to the plasma membrane of cultured CHO cells. The results suggest that the cytoplasmic domain of TGFα is required for autocrine parenchymal tumor formation in the pituitary gland. This signal cannot be inhibited by the EGFR-tr. Conversely, the released form of TGFα appears to have primarily paracrine activity.

Original languageEnglish (US)
Pages (from-to)231-242
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1743
Issue number3
DOIs
StatePublished - Apr 15 2005

Fingerprint

Transforming Growth Factors
Membranes
Epidermal Growth Factor Receptor
Pituitary Gland
Hyperplasia
Phenotype
CHO Cells
Pituitary Neoplasms
Transgenic Mice
Cultured Cells
Cell Membrane
Pathology
Messenger RNA

Keywords

  • Adenoma
  • Fibrosis
  • Hyperplasia
  • Pituitary

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Proteolytic processing of TGFα redirects its mitogenic activity : The membrane-anchored form is autocrine, the secreted form is paracrine. / Roh, Meejeon; Paterson, Andrew J.; Liu, Kan; McAndrew, Joanne; Chin, Edward; Kudlow, Jeffrey E.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1743, No. 3, 15.04.2005, p. 231-242.

Research output: Contribution to journalArticle

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