The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras.
Transmembrane proteins of the tetraspanin superfamily are associated with integrins and are thought to regulate adhesion-dependent signaling. The molecular mechanisms of this regulation remain unknown. We used rat fibroblasts to analyze the contribution of the tetraspanin CD151 in the adhesion-dependent signaling. Expression of CD151 specifically attenuated adhesion-dependent activation of Ras. Furthermore, activation of PKB/c-Akt and ERK1/2, downstream targets in the Ras signaling pathway, was also diminished in cells expressing CD151. In contrast, adhesion-dependent activation of FAK and c-Src were not affected by CD151. The attenuation of Ras signaling did not correlate with phosphorylation of Tyr925-FAK, tyrosine phosphorylation of Shc, or with assembly of the p120RasGAP-p62Dok complex. Using mutants of CD151 we established that the cytoplasmic C-terminal portion is critical for activity of CD151 toward Ras. Taken together these results identify CD151 as a negative regulator of Ras and suggest a novel mechanism of adhesion-dependent regulation of Ras activity.
Sawada
Shigeaki
S
Cancer Research UK Institute for Cancer Studies and School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom.
Yoshimoto
Mitsunori
M
Odintsova
Elena
E
Hotchin
Neil A
NA
Berditchevski
Fedor
F
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000378:metabolism; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D060185:Tetraspanin 24; D014162:Transfection; D020729:p120 GTPase Activating Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D015703:Antigens, CD; C554717:Cd151 protein, rat; D016023:Integrins; D011994:Recombinant Proteins; D060185:Tetraspanin 24; D020729:p120 GTPase Activating Protein; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D018631:ras Proteins