Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP

Elina Mattila, Teijo Pellinen, Jonna Nevo, Karoliina Vuoriluoto, Antti Arjonen, Johanna Ivaska (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

130 Citations (Scopus)

Abstract

Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and cross-talk between different cellular signalling pathways1. So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling2,3,4. Here we show that a collagen-binding integrin α1β1 functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of α1 integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen. The activation results in reduced EGFR phosphorylation after EGF stimulation. Introduction of the α1 cytoplasmic domain peptide into cells induces phosphatase activation and inhibits EGF-induced cell proliferation and anchorage-independent growth of malignant cells. These data are the first demonstration of the regulation of TCPTP activity in vivo and represent a new molecular paradigm of integrin-mediated negative regulation of receptor tyrosine kinase signalling.
Original languageEnglish
Pages (from-to)78 - 85
Number of pages8
JournalNature Cell Biology
Volume7
Issue number1
DOIs
Publication statusPublished - 2005
MoE publication typeA1 Journal article-refereed

Fingerprint

Non-Receptor Type 2 Protein Tyrosine Phosphatase
Protein Tyrosine Phosphatases
Epidermal Growth Factor Receptor
Integrins
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor
Cell Adhesion
Collagen
Phosphoric Monoester Hydrolases
Phosphorylation
Cell Proliferation
protein phosphatase-T
Growth

Keywords

  • integrin
  • cell adhesion
  • negative regulator
  • epidermal growth factor receptor
  • tyrosine
  • TCPTP

Cite this

Mattila, Elina ; Pellinen, Teijo ; Nevo, Jonna ; Vuoriluoto, Karoliina ; Arjonen, Antti ; Ivaska, Johanna. / Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP. In: Nature Cell Biology. 2005 ; Vol. 7, No. 1. pp. 78 - 85.
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Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP. / Mattila, Elina; Pellinen, Teijo; Nevo, Jonna; Vuoriluoto, Karoliina; Arjonen, Antti; Ivaska, Johanna (Corresponding Author).

In: Nature Cell Biology, Vol. 7, No. 1, 2005, p. 78 - 85.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Mattila, Elina

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AU - Arjonen, Antti

AU - Ivaska, Johanna

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AB - Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and cross-talk between different cellular signalling pathways1. So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling2,3,4. Here we show that a collagen-binding integrin α1β1 functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of α1 integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen. The activation results in reduced EGFR phosphorylation after EGF stimulation. Introduction of the α1 cytoplasmic domain peptide into cells induces phosphatase activation and inhibits EGF-induced cell proliferation and anchorage-independent growth of malignant cells. These data are the first demonstration of the regulation of TCPTP activity in vivo and represent a new molecular paradigm of integrin-mediated negative regulation of receptor tyrosine kinase signalling.

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