The PKCalpha-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals.
Protein kinase C (PKC) is a key regulator of cell proliferation, differentiation, and apoptosis and is one of the drug targets of anticancer therapy. Recently, a single point mutation (D294G) in PKCalpha has been found in pituitary and thyroid tumors with more invasive phenotype. Although the PKCalpha-D294G mutant is implicated in the progression of endocrine tumors, no apparent biochemical/cell biological abnormalities underlying tumorigenesis with this mutant have been found. We report here that the PKCalpha-D294G mutant is unable to bind to cellular membranes tightly despite the fact that it translocates to the membrane as efficiently as the wild-type PKCalpha upon treatment of phorbol ester. The impaired membrane binding is associated with this mutant's inability to transduce several antitumorigenic signals as it fails to mediate phorbol ester-stimulated translocation of myristoylated alanine-rich protein kinase C substrate (MARCKS), to activate mitogen-activated protein kinase and to augment melatonin-stimulated neurite outgrowth. Thus, the PKCalpha-D294G is a loss-of-function mutation. We propose that the wild-type PKCalpha may play important antitumorigenic roles in the progression of endocrine tumors. Therefore, developing selective activators instead of inhibitors of PKCalpha might provide effective pharmacological interventions for the treatment of certain endocrine tumors.
Zhu
Yimin
Y
Department of Biochemistry, Faculty of Science, The National University of Singapore, Singapore, Singapore.
Dong
Qihan
Q
Tan
Bee Jen
BJ
Lim
Wee Guan
WG
Zhou
Shufeng
S
Duan
Wei
W
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002462:Cell Membrane / Q000201:enzymology; D006224:Cricetinae; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016501:Neurites / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D051571:Protein Kinase C-alpha; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D008550:Melatonin; D013755:Tetradecanoylphorbol Acetate