SUMMARY The structural modification of dendritic spines plays a critical role in synaptic plasticity. CaMKII is a pivotal molecule involved in this process through both kinase-dependent and independent structural functions, but the respective contributions of these two functions to the synaptic plasticity remain unclear. We demonstrate that the transient interplay between the kinase and structural functions of CaMKII during the induction of synaptic plasticity temporally gates the activity-dependent modification of the actin cytoskeleton. Inactive CaMKII binds F-actin, thereby limiting access of actin regulating proteins to F-actin and stabilizing spine structure. CaMKII-activating stimuli trigger dissociation of CaMKII from F-actin through specific autophosphorylation reactions within the F-actin binding region and permits F-actin remodeling by regulatory proteins followed by reassociation and restabilization. Blocking the autophosphorylation impairs both functional and structural plasticity without affecting kinase activity. These results underpin the importance of the interplay between the kinase and structural functions of CaMKII in defining a time window permissive for synaptic plasticity.

The activation of Fli-1, an Ets transcription factor, is the critical genetic event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. Fli-1 overexpression leads to erythropoietin-dependent erythroblast proliferation, enhanced survival, and inhibition of terminal differentiation, through activation of the Ras pathway. However, the mechanism by which Fli-1 activates this signal transduction pathway has yet to be identified. Down-regulation of the Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with erythropoietin-stimulated IntroductionThe progression of cancer is a multistep process in which oncogenes and tumor suppressor genes mediate changes in gene expression required for malignant transformation. Transcription factors, often described as oncogenes or tumor suppressor genes, play a pivotal role within signal transduction pathways governing cellular proliferation, differentiation, and apoptosis. 1 In Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, the transcription factor fli-1 is activated as a result of proviral integration. A proto-oncogene and member of the Ets family of transcription factors, fli-1 plays a critical role in normal development, hematopoiesis and oncogenesis. [2][3][4][5][6] Accordingly, a recent study from our group, and that of another laboratory, has demonstrated that Fli-1 inhibition suppresses growth and induces cell death in murine and human erythroleukemias. 7,8 Fli-1 overexpression in erythroblasts blocks erythroid differentiation that is associated with activation of the Shc/Ras pathway in response to erythropoietin (Epo) stimulation. 9 The Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with phosphorylated Shc in Epo-stimulated erythroleukemic cells, 9 and correlates with increased proliferation of transformed erythroid cells. 10 Because SHIP-1 is involved in the regulation of extracellular signal-regulated kinase/mitogenactivated protein kinase (ERK/MAPK) and phosphatidylinositol 3-kinase (PI 3-K) signaling pathways, 11,12 we hypothesized that Fli-1 may promote Epo-induced proliferation, and activation of the above mentioned pathways, in part, through regulation of SHIP-1.SHIP-1 plays a role in the activation and proliferation of myeloid cells, macrophages, and mast cells. This phosphatase also negatively regulates c-Jun NH2-terminal kinase (JNK), 13 and nuclear factor-B (NF-B) activity. 14 SHIP-1 is expressed exclusively in hematopoietic cells and developing spermatogonia and is activated after cytokine, growth factor, or immunoreceptor activation in hematopoietic cells. 12,14,15 SHIP-1 is expressed in mature T cells, granulocytes, monocytes/macrophages, mast cells, and platelets. 16 Interestingly, it has been documented that SHIP-1 expression is turned off during erythropoiesis, specifically in TER119ϩ erythroid cells. 15 Expression of a short form of SHIP-1 (termed s-SHIP) modulates the activation threshold of primitive stem cells. 17,18 SHIP-1 knockout mice are viable b...