Negative regulation of EGFR signalling through integrin-alpha1beta1-mediated activation of protein tyrosine phosphatase TCPTP.
Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and cross-talk between different cellular signalling pathways. So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling. Here we show that a collagen-binding integrin alpha(1)beta(1) functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of alpha(1) 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 alpha(1) 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.
Mattila
Elina
E
VTT Technical Research Centre of Finland, Medical Biotechnology and University of Turku Centre for Biotechnology, Turku FIN-20520, Finland.
Pellinen
Teijo
T
Nevo
Jonna
J
Vuoriluoto
Karoliina
K
Arjonen
Antti
A
Ivaska
Johanna
J
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism*; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D039222:Integrin alpha1beta1; D004815:Epidermal Growth Factor; D003094:Collagen; D066246:ErbB Receptors; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse