Trends in Biochemical Sciences
ReviewThe Ca2+–calmodulin-dependent protein kinase cascade
Section snippets
Structure and regulation of the kinases
Each member of the CaM-kinase cascade has a catalytic domain adjacent to a regulatory region that contains an overlapping autoinhibitory domain (AID) and the CaM-binding domain (CBD; see Fig. 2). These domains have been defined through site-specific mutation and deletion analyses. An interaction between the AID and the catalytic domain maintains the kinase in an inactive conformation by preventing binding of protein substrate as well as Mg2+–ATP (Ref. 3). Binding of Ca2+–CaM to the CBD alters
Activation of Ca2+–calmodulin-dependent kinases by phosphorylation
Although CaMKI and CaMKIV can be potently activated by the binding of Ca2+–CaM, early studies indicated that the kinases purified from brain16, 17, but not recombinant CaMKIV18, 19, could be further activated by phosphorylation. These results suggested that activation was not due to autophosphorylation, and separate activating kinases were identified19, 20, 21. Our group5 cloned αCaMKK, which can activate both CaMKI and CaMKIV (Fig. 3), and, more recently, Kitani et al.6 and Anderson et al.7
Downstream substrates of Ca2+–calmodulin-dependent kinases
In vitro, CaMKI can phosphorylate synapsin31 and the cystic fibrosis transmembrane regulator32, but its physiological substrates are not clear. Another possible substrate is the transcription factor CREB: transfected CaMKI can stimulate CREB-dependent transcription33. This might be artefactual, because endogenous CaMKI has not been detected in the nucleus2; alternatively, a unique nuclear isoform of CaMKI might exist. CaMKIV shows very strong nuclear localization4, and good evidence supports
Cross-talk with other signaling pathways
There appear to be multiple mechanisms for cross-talk between the CaM-kinase cascade and other signaling pathways (Fig. 1). For example, PKA can phosphorylate two sites in CaMKK and inhibit its activity43. One of these sites is in the CBD of CaMKK. This pathway depends on the temporal sequence of stimulation. For example, prior treatment of cultured cells with forskolin (which elevates cAMP levels and stimulates PKA activity) strongly inhibits Ca2+-mobilization-induced activation of CaMKK and
Regulation of apoptosis
Recent work suggests that the CaM-kinase cascade modulates apoptosis through two putative mechanisms. Overexpression of an inactive form of CaMKIV, which probably acts in a dominant negative manner, significantly increases apoptosis in T cells38. This increased level of apoptosis could be due to the suppression of CREB phosphorylation in these cells38, given that dominant negative CREB can also promote T-cell apoptosis47. Alternatively, the overexpressed inactive CaMKIV might bind to and
Outlook
Studies over the past five years have begun to characterize the members of the CaM-kinase cascade and their physiological roles. Future studies will probably find more members of this cascade and document additional cellular roles. Several questions remain. For example, is CaMKIV-mediated phosphorylation of CREB or other transcription factors important for late-phase synaptic plasticity, such as long-term depression in the cerebellum or long-term potentiation in the hippocampus? Are members of
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