Overexpression of the signaling adapter FRS2 reconstitutes the cell cycle deficit of a nerve growth factor non-responsive TrkA receptor mutant.
We have characterized the cell cycle deficit of a novel TrkA receptor mutant (TrkAS3) that fails to support nerve growth factor (NGF)-dependent cell cycle arrest and neurite outgrowth. TrkAS3 receptors fail to support an NGF-dependent increase in the expression of cyclin D1 and the cell cycle inhibitor, p21(Waf1/Cip1), two important regulators of G(1) /S transition, and do not down-regulate expression of the G(2) /M phase marker, cdc2/cdk1, or the S phase marker, proliferating cell nuclear antigen. Moreover, NGF-activated TrkAS3 receptors do not down-regulate cyclin-dependent kinase 4 phosphorylation of the retinoblastoma protein, essential for G(1) arrest, in comparison to NGF-activated wild-type TrkA. Collectively these data indicate that TrkAS3 receptors fail to support NGF-dependent G(1) arrest. Interestingly, ectopic expression of regulators of G(1) /S arrest, such as cyclin D1 or inhibitors of cell cycle (p21(Waf1/Cip1), p16(INK4A) ), or the fibroblast growth factor (FGF) receptor substrate-2 (FRS2) in cells expressing TrkAS3 reconstitutes NGF-dependent neurite outgrowth. Collectively, these data suggest a model in which NGF-stimulated TrkA-dependent activation of FRS2 supports neurite outgrowth through a mechanism that likely involves the induction of p21(Waf1/Cip1) expression and the arrest of cells at G(1) /S.
Zeng
Guoqian
G
Laboratory of Neural Signaling, The John P. Robarts Research Institute, 100 Perth Drive, London, Ontario N6A 5K8, Canada.
Meakin
Susan O
SO
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016716:PC12 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C106534:FRS2 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D018844:Cyclin-Dependent Kinases