A two-dimensional ERK-AKT signaling code for an NGF-triggered cell-fate decision.
Growth factors activate Ras, PI3K, and other signaling pathways. It is not well understood how these signals are translated by individual cells into a decision to proliferate or differentiate. Here, using single-cell image analysis of nerve growth factor (NGF)-stimulated PC12 cells, we identified a two-dimensional phospho-ERK (pERK)-phospho-AKT (pAKT) response map with a curved boundary that separates differentiating from proliferating cells. The boundary position remained invariant when different stimuli were used or upstream signaling components perturbed. We further identified Rasa2 as a negative feedback regulator that links PI3K to Ras, placing the stochastically distributed pERK-pAKT signals close to the decision boundary. This allows for uniform NGF stimuli to create a subpopulation of cells that differentiates with each cycle of proliferation. Thus, by linking a complex signaling system to a simpler intermediate response map, cells gain unique integration and control capabilities to balance cell number expansion with differentiation.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Jia-Yun
JY
Chen
Jia-Ren
JR
Lin
Karlene A
KA
Cimprich
Tobias
T
Meyer
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020935:MAP Kinase Signaling System; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D020703:ras GTPase-Activating Proteins / Q000378:metabolism / Q000502:physiology
D056741:Cyclin D; D020703:ras GTPase-Activating Proteins; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases