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We have isolated, from a human tumor cDNA library, a gene encoding a putative receptor-like proteintyrosine kinase that we call TK14. The amino acid sequence of the TK14 protein is closely related to the available partial sequence of the mouse protein bek, and more distantly related to the sequences of a chicken basic fibroblast growth factor receptor (73% sequence homology) and the apparent human equivalent of this receptor, the FLG protein (encoded by the fins-like tyrosine kinase gene). Overexpression of the TK14 protein by transfection of COS-1 cells with the corresponding cDNA in a simian virus 40-based expression vector leads to the appearance of new cell-surface binding sites for both acidic and basic fibroblast growth factors. This has been demonstrated by specific binding assays and chemical cross-linking experiments using 1,I-labeled growth factors. It appears, therefore, that the human genome contains at least two distinct genes, for TK14 and FLG, that code for related fibroblast growth factor receptors.

Here we show that brain-derived neurotrophic factor (BDNF) stimulates both the phosphorylation of the Ca 2؉ /calmodulin-dependent protein kinase 2 (CaMK2) and its kinase activity in rat hippocampal slices. In addition, we find that: (i) the time course of BDNF action is not accompanied by a change in the spectrum of either ␣-and ␤-subunits of CaMK2 detected by immunoblotting; (ii) both treatment of solubilized CaMK2 with alkaline phosphatase and treatment of immunoprecipitated CaMK2 with protein phosphatase 1 reverse phosphorylation and activation of the kinase; (iii) phospholipase C inhibitor D609 and intracellular Ca 2؉ chelation by 1,2-bis-(o-aminophenoxy)ethane-N,N,N ,N ,-tetracetic acid tetra(acetoxymethyl)ester or 8-(diethylamino)octyl-3, 4,5-trimethoxybenzoate but not omission of Ca 2؉ or Ca 2؉ chelation by EGTA, abolish the stimulatory effect of BDNF on phosphorylation and activation of CaMK2. These results strongly suggest that the conversion of CaMK2 into its active, autophosphorylated form, but not its concentration, is increased by BDNF via stimulation of phospholipase C and subsequent intracellular Ca 2؉ mobilization.Ca 2ϩ /calmodulin-dependent protein kinase 2 (CaMK2) 1 is a major neuronal mediator of calcium signaling that integrates multiple related functions. It has been implicated in a variety of events in neurons, ranging from the neurotransmitter synthesis and release, modulation of neurotransmitter receptors and ionic channels, and gene expression to several aspects of synaptic plasticity such as the prevailing model for memory called long term potentiation as well as spatial learning (1-4). The distinctive property of CaMK2 is that the Ca 2ϩ /calmodulin-activated enzyme rapidly autophosphorylates, thereby generating a constitutively active, phosphorylated Ca 2ϩ -independent kinase that phosphorylates multiple substrates at presynaptic and postsynaptic sites. Studies have shown that certain neurotransmitters are of critical importance in the modulation of this activation reaction (2). However, whether activation of CaMK2 can be due to other signaling factors still remains unclear.In addition to the characteristic trophic and phenotypic effects of trophic factors, it has been recently shown that neurotrophins strongly enhance synaptic efficacy. For example, brain-derived neurotrophic factor (BDNF) induces an increase of synaptic transmission in rat hippocampal cultures and slices (5, 6). Furthermore, consistent with BDNF knockout studies (7), a critical level of BDNF activity was found to be important for long term potentiation in hippocampus (8). However, little is known about how the neurotrophins might modulate synaptic plasticity. It is therefore of great interest to examine whether CaMK2 might be also capable of orchestrating these trophic responses. Here, we have investigated the effects of BDNF on the Ca 2ϩ -dependent CaMK2 activity in hippocampal slices of adult rat. EXPERIMENTAL PROCEDURESMaterials and Reagents-The materials and reagents were obtained as follows: [␥-32 P]ATP and ECL ...

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