β4 integrin is a transforming molecule that unleashes Met tyrosine kinase tumorigenesis

Andrea Bertotti, Paolo M. Comoglio, Livio Trusolino

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Cell multiplication in the absence of integrin-derived adhesive signals (anchorage-independent growth) is the phenotypic hallmark of neoplastic transformation. Therefore, the frequently observed up-regulation of some integrins in tumors has been interpreted as an epiphenomenon and not as a causative factor of oncogenic conversion. β4 integrin stimulates proliferation and survival of epithelial cells and is overexpressed in human carcinomas, often in concomitance with up-regulation of the Met tyrosine kinase receptor for hepatocyte growth factor. Met is not endowed with transforming ability but can exploit the β4 cytoplasmic tail as a substrate/adaptor for amplification of mitogenic and antiapoptotic responses, independently of cell adhesion. Here, we show that overexpression of β4 is sufficient to transform rodent fibroblasts, enhances anchorage-independent growth of breast carcinoma cells, and induces tumorigenesis in nude mice; conversely, RNA interference-mediated depletion abrogates the transformed phenotype of neoplastic cells. These autonomous oncogenic properties are dramatically exacerbated upon Met coexpression, suggesting that the integrin can instigate the latent tumorigenic potential of the kinase. A β4 nonadhesive variant still cooperates with Met for cellular transformation, confirming the adhesion-independent function of β4 in magnification of Met biological effects. Conversely, a β4 signaling-incompetent mutant that cannot be efficiently tyrosine phosphorylated by Met and displays reduced ability to activate phosphatidylinositol 3-kinase-dependent and Ras-dependent pathways aborts transformation. Our findings define β4 as a signaling accomplice (a "servo-oncogene") of tyrosine kinase proto-oncogenes in primary carcinogenesis, evoke an unorthodox function for a prototypic adhesion molecule in the positive regulation of anchorage-independent growth, and suggest the use of β4 as a target for anticancer therapy.

Original languageEnglish
Pages (from-to)10674-10679
Number of pages6
JournalCancer Research
Volume65
Issue number23
DOIs
Publication statusPublished - Dec 1 2005

Fingerprint

Integrins
Protein-Tyrosine Kinases
Carcinogenesis
Up-Regulation
Growth
Phosphatidylinositol 3-Kinase
Hepatocyte Growth Factor
Proto-Oncogenes
Receptor Protein-Tyrosine Kinases
RNA Interference
Oncogenes
Nude Mice
Cell Adhesion
Adhesives
Tyrosine
Tail
Rodentia
Phosphotransferases
Fibroblasts
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

β4 integrin is a transforming molecule that unleashes Met tyrosine kinase tumorigenesis. / Bertotti, Andrea; Comoglio, Paolo M.; Trusolino, Livio.

In: Cancer Research, Vol. 65, No. 23, 01.12.2005, p. 10674-10679.

Research output: Contribution to journalArticle

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