Contingent Phosphorylation/Dephosphorylation Provides a Mechanism of Molecular Memory in WASP

Cornell University, Итак, New York, United States
Molecular Cell (Impact Factor: 14.02). 06/2003; 11(5):1215-27. DOI: 10.1016/S1097-2765(03)00139-4
Source: PubMed


Cells can retain information about previous stimuli to produce distinct future responses. The biochemical mechanisms by which this is achieved are not well understood. The Wiskott-Aldrich syndrome protein (WASP) is an effector of the Rho-family GTPase Cdc42, whose activation leads to stimulation of the actin nucleating assembly, Arp2/3 complex. We demonstrate that efficient phosphorylation and dephosphorylation of WASP at Y291 are both contingent on binding to activated Cdc42. Y291 phosphorylation increases the basal activity of WASP toward Arp2/3 complex and enables WASP activation by new stimuli, SH2 domains of Src-family kinases. The requirement for contingency in both phosphorylation and dephosphorylation enables long-term storage of information by WASP following decay of GTPase signals. This biochemical circuitry allows WASP to respond to the levels and timing of GTPase and kinase signals. It provides mechanisms to specifically achieve transient or persistent actin remodeling, as well as long-lasting potentiation of actin-based responses to kinases.

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Available from: Eduardo M Torres, Sep 24, 2014
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    • "TOCA family members are also essential for activation of N-WASP/WASP downstream of CDC42. However, removal of CIP4 did not alter EGF-mediated activation of N-WASP, monitored by measuring its tyrosine phosphorylation (Torres and Rosen, 2003) (Figure S3G), suggesting that this latter pathway "
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    • "Using Lck-deficient Jurkat cells (JCam-1) and primary T cells deficient for Itk, Lck, or Fyn, Badour et al. has identified that Fyn, but not Itk or Lck, is required for WASP phosphorylation at Tyr291 after TCR stimulation in both Jurkat and primary T cells [45]. Previous studies suggested that SLP-76, as a scaffolding protein, brings WASP into proximity with Cdc42-GTP, and that this Cdc-GTP binding is required for Fyn-regulated phosphorylation of WASP at Tyr291 [61], [62]. We hypothesize that SLP-76 mediates scaffolding of the interaction between WASP and Fyn and therefore the absence of SLP-76 resulted in the significantly reduced phosphorylation of WASP at Tyr291 in SLP-76 deficient cells (Figure 7C), but this hypothesis would have to be validated by future experiments. "
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