TAILIEUCHUNG - Báo cáo khoa học: Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle

Src-family kinases (SFKs) play a pivotal role in growth factor signaling, mitosis, cell motility and invasiveness. In their basal state, SFKs maintain a closed autoinhibited conformation, where the Src homology 2 domain inter-acts with an inhibitory phosphotyrosine in the C-terminus. | ễFEBS Journal Toggle switches pulses and oscillations are intrinsic properties of the Src activation deactivation cycle Nikolai P. Kaimachnikov1 2 and Boris N. Kholodenko1 3 1 Department of Pathology Anatomy and CellBiology Thomas Jefferson University Philadelphia PA USA 2 Institute of CellBiophysics Russian Academy of Sciences Pushchino Moscow Region Russia 3 Systems Biology Ireland University College Dublin Ireland Keywords autophosphorylation bistability excitable behavior oscillations Src-family kinases Correspondence B. N. Kholodenko Systems Biology Ireland University College Dublin Belfield Dublin 4 Ireland Fax 353 1 716 6713 Tel 353 1 716 6919 E-mail Note The mathematical model described here has been submitted to the Online Cellular Systems Modelling Database and can be accessed at http database kaimachnikov Received 5 December 2008 revised 16 April 2009 accepted 28 May 2009 doi Src-family kinases SFKs play a pivotal role in growth factor signaling mitosis cell motility and invasiveness. In their basal state SFKs maintain a closed autoinhibited conformation where the Src homology 2 domain interacts with an inhibitory phosphotyrosine in the C-terminus. Activation involves dephosphorylation of this inhibitory phosphotyrosine followed by intermolecular autophosphorylation of a specific tyrosine residue in the activation loop. The spatiotemporal dynamics of SFK activation controls cell behavior yet these dynamics remain largely uninvestigated. In the present study we show that the basic properties of the Src activation deactivation cycle can bring about complex signaling dynamics including oscillations toggle switches and excitable behavior. These intricate dynamics do not require imposed external feedback loops and occur at constant activities of Src inhibitors and activators such as C-terminal Src kinase and receptortype protein tyrosine phosphatases. We demonstrate that

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