c-Src activation by the E5 oncoprotein enables transformation independently of PDGF receptor activation.
The E5 oncoprotein of bovine papillomavirus type 1 is a Golgi-resident, hydrophobic polypeptide that can transform immortalized fibroblasts by activating endogenous platelet-derived growth factor receptor beta (PDGF-R). However, the existence of E5 mutants that dissociate transformation from PDGF-R activation implies that there are additional mechanism(s) by which E5 can transform cells. We now show that both wt E5, and transforming E5 mutants that are defective for PDGF-R activation, constitutively activate endogenous c-Src in NIH3T3 cell lines to levels normally associated with acute growth factor stimulation. The ubiquitous Src family protein tyrosine kinase (PTK) Fyn is not activated by these E5 constructs, nor are focal adhesion kinase and endogenous receptor PTKs for insulin, epidermal growth factor, basic fibroblast growth factor and insulin-like growth factor. We further demonstrate that transforming activity of the L26A E5 mutant, which is highly defective for PDGF-R activation, depends on its ability to activate Src. L26A E5 does not transform SYF cells that are deficient for Src, Fyn and Yes, unless Src expression is reconstituted, and does not transform NIH3T3 cells in which Src PTK activity is maintained at a basal level by means of kinase-defective K295R Src overexpression.
Suprynowicz
Frank A
FA
Department of Pathology, Georgetown University Medical Center, Washington, DC 20007, USA.
Baege
Astrid
A
Sunitha
Iruvanti
I
Schlegel
Richard
R
D016475:3T3 Cells; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D009856:Oncogene Proteins, Viral; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; C054304:oncogene protein E5, Bovine papillomavirus type 1; C496051:Ptk2 protein, mouse