TY - JOUR
T1 - Cell fate decisions are specified by the dynamic ERK interactome
AU - Von Kriegsheim, Alex
AU - Baiocchi, Daniela
AU - Birtwistle, Marc
AU - Sumpton, David
AU - Bienvenut, Willy
AU - Morrice, Nicholas
AU - Yamada, Kayo
AU - Lamond, Angus
AU - Kalna, Gabriella
AU - Orton, Richard
AU - Gilbert, David
AU - Kolch, Walter
N1 - Funding Information:
We thank P. Mortensen for help with MSQuant, A. Pitt and C. Ward for help with MS, O.Rath for the design of primers and G. Cesareni and A. Chatraryamontri for help with submission of the interaction data to the IMEx consortium through MINT. The work was supported by the European Union Interaction Proteome project (LSHG-CT-2003-505520), the RASOR project (BBSRC and EPSRC) and Cancer Research UK.
PY - 2009/12
Y1 - 2009/12
N2 - Extracellular signal-regulated kinase (ERK) controls fundamental cellular functions, including cell fate decisions. In PC12, cells shifting ERK activation from transient to sustained induces neuronal differentiation. As ERK associates with both regulators and effectors, we hypothesized that the mechanisms underlying the switch could be revealed by assessing the dynamic changes in ERK-interacting proteins that specifically occur under differentiation conditions. Using quantitative proteomics, we identified 284 ERK-interacting proteins. Upon induction of differentiation, 60 proteins changed their binding to ERK, including many proteins that were not known to participate in differentiation. We functionally characterized a subset, showing that they regulate the pathway at several levels and by different mechanisms, including signal duration, ERK localization, feedback, crosstalk with the Akt pathway and differential interaction and phosphorylation of transcription factors. Integrating these data with a mathematical model confirmed that ERK dynamics and differentiation are regulated by distributed control mechanisms rather than by a single master switch.
AB - Extracellular signal-regulated kinase (ERK) controls fundamental cellular functions, including cell fate decisions. In PC12, cells shifting ERK activation from transient to sustained induces neuronal differentiation. As ERK associates with both regulators and effectors, we hypothesized that the mechanisms underlying the switch could be revealed by assessing the dynamic changes in ERK-interacting proteins that specifically occur under differentiation conditions. Using quantitative proteomics, we identified 284 ERK-interacting proteins. Upon induction of differentiation, 60 proteins changed their binding to ERK, including many proteins that were not known to participate in differentiation. We functionally characterized a subset, showing that they regulate the pathway at several levels and by different mechanisms, including signal duration, ERK localization, feedback, crosstalk with the Akt pathway and differential interaction and phosphorylation of transcription factors. Integrating these data with a mathematical model confirmed that ERK dynamics and differentiation are regulated by distributed control mechanisms rather than by a single master switch.
UR - http://www.scopus.com/inward/record.url?scp=73349139547&partnerID=8YFLogxK
U2 - 10.1038/ncb1994
DO - 10.1038/ncb1994
M3 - Article
C2 - 19935650
AN - SCOPUS:73349139547
SN - 1465-7392
VL - 11
SP - 1458
EP - 1464
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 12
ER -