E5 oncoprotein mutants activate phosphoinositide 3-kinase independently of platelet-derived growth factor receptor activation.
The E5 oncoprotein of bovine papillomavirus type 1 is a Golgi-resident, 44-amino acid polypeptide that can transform fibroblast cell lines by activating endogenous platelet-derived growth factor receptor beta (PDGF-R). However, the recent discovery of E5 mutants that exhibit strong transforming activity but minimal PDGF-R tyrosine phosphorylation indicates that E5 can potentially use additional signal transduction pathway(s) to transform cells. We now show that two classes of E5 mutants, despite poorly activating the PDGF-R, induce tyrosine phosphorylation and activation of phosphoinositide 3-kinase (PI 3-K) and that this activation is resistant to a selective inhibitor of PDGF-R kinase activity, tyrphostin AG1296. Consistent with this independence from PDGF-R signaling, the E5 mutants fail to induce significant cell proliferation in the absence of PDGF, unlike wild-type E5 or the sis oncoprotein. Despite differences in growth factor requirements, however, both wild-type E5 and mutant E5 cell lines form colonies in agarose. Interestingly, activation of PI 3-K occurs without concomitant activation of the ras-dependent mitogen-activated protein kinase pathway. The known ability of constitutively activated PI 3-K to induce anchorage-independent cell proliferation suggests a mechanism by which the mutant E5 proteins transform cells.
Suprynowicz
F A
FA
Department of Pathology, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Sparkowski
J
J
Baege
A
A
Schlegel
R
R
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017479:Receptors, Platelet-Derived Growth Factor / Q000819:agonists* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D009856:Oncogene Proteins, Viral; C054304:oncogene protein E5, Bovine papillomavirus type 1; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor