TY - JOUR
T1 - Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis
AU - Bardelli, Alberto
AU - Basile, Maria Lisa
AU - Audero, Enrica
AU - Giordano, Silvia
AU - Wennström, Stefan
AU - Ménard, Sylvie
AU - Comoglio, Paolo M.
AU - Ponzetto, Carola
PY - 1999/2/4
Y1 - 1999/2/4
N2 - The Met tyrosine kinase - the HGF receptor - induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met(2xGrb2)) is permissive for motility, increases transformation, but - surprisingly - is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met(2xP13K) or p85 and Grb2 (Met(P13K/Grb2)) to evaluate the relative importance of Pas and PI 3-kinase as downstream effectors of Met. Met(2xP13K) competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met(P13K/Grb2) induced motility, transformation, invasion and metastasis as efficiently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met(2xGrb2) mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.
AB - The Met tyrosine kinase - the HGF receptor - induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met(2xGrb2)) is permissive for motility, increases transformation, but - surprisingly - is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met(2xP13K) or p85 and Grb2 (Met(P13K/Grb2)) to evaluate the relative importance of Pas and PI 3-kinase as downstream effectors of Met. Met(2xP13K) competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met(P13K/Grb2) induced motility, transformation, invasion and metastasis as efficiently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met(2xGrb2) mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.
KW - Grb2
KW - Met signaling
KW - Met-mediated metastasis
KW - PI 3-kinase
KW - Ras
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U2 - 10.1038/sj.onc.1202607
DO - 10.1038/sj.onc.1202607
M3 - Article
C2 - 10022119
AN - SCOPUS:0033521924
VL - 18
SP - 1139
EP - 1146
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 5
ER -