The ShcA adaptor activates AKT signaling to potentiate breast tumor angiogenesis by stimulating VEGF mRNA translation in a 4E-BP-dependent manner.
The ShcA adaptor protein is engaged by numerous receptor tyrosine kinases (RTKs) in breast cancer cells. Once activated, RTKs phosphorylate three key tyrosine phosphorylation sites (Y239, Y240 and Y317) within ShcA that creates a docking site for Grb2/SOS and Grb2/Gab-containing complexes to activate the MAPK and AKT signaling pathways, respectively. We previously demonstrated that a tyrosine to phenylalanine substitution of the ShcA tyrosine phosphorylation sites (Shc3F-Y239/240/313F) significantly impairs breast tumor growth and angiogenesis in transgenic mouse models, in part, through the regulation of vascular endothelial growth factor (VEGF) production. Despite this fact, the underlying molecular mechanisms by which ShcA transduces pro-tumorigenic signals in breast cancer cells remain poorly defined. In this study, we demonstrate that ShcA-dependent activation of AKT, but not the RAS/MAPK pathway, induces VEGF production by bolstering VEGF mRNA translation. Accordingly, ShcA drives breast tumor growth and angiogenesis in vivo in a 4E-BP-dependent manner. These findings establish ShcA as a biological bridge that links AKT activation downstream of RTKs to cap-dependent VEGF mRNA translation in order to promote mammary tumorigenesis.
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
Y K
YK
Im
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
R
R
La Selva
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
V
V
Gandin
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
J R
JR
Ha
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
V
V
Sabourin
Goodman Cancer Research Centre, Montreal, Quebec, Canada.
N
N
Sonenberg
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
T
T
Pawson
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
I
I
Topisirovic
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
J
J
Ursini-Siegel
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply*; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D042461:Vascular Endothelial Growth Factor A; C087000:EIF4EBP1 protein, human; C528024:SHC1 protein, human; C122029:SHC3 protein, human