Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression.

Abstract

Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA) leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues, may act as a mediator of Ca(2+)-dependent gene induction.

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

“…See Discussion for details cAMP-dependent protein kinase (De Cesare et al, 1999;Montminy, 1997). They can also be activated by phosphorylation at the same site by calcium calmodulin dependent protein kinase and RSK1, 2 and 3 as well as the RSK-related kinase MSK1 (Deak et al, 1998;Matthews et al, 1994;Pierrat et al, 1998;Xing et al, 1996Xing et al, , 1998. The RSK family can be phosphorylated and activated by ERK MAP kinases while MSK1 can be activated by either ERK or p38 (Deak et al, 1998;Pierrat et al, 1998;Xing et al, 1996Xing et al, , 1998.…”

“…Each is phosphorylated on a conserved serine (amino acid 133 in CREB and 63 in ATF1) that causes activation of the factors (Gonzalez and Montminy, 1989;Rehfuss et al, 1991). This site is phosphorylated by cAMP-dependent protein kinase (PKA) and calcium-calmodulin dependent protein kinase (CaMK) which mediate cAMP and calcium induction, respectively (Liu et al, 1993;Matthews et al, 1994;Montminy, 1997). Growth factorand stress-induced pathways can also activate CREB through phosphorylation of serine 133.…”

Visualizing dynamic interaction between calmodulin and calmodulin-related kinases via a monitoring method in live mammalian cells

“…In CREB-mediated transcription, the c-fos promoter, one of first identified promoters regulated by CREB, is regulated by CaMKI, IV and II (15). Interestingly, CaMKI and IV can stimulate the expression of the c-fos gene, while CaMKIIα inhibits transcription by phosphorylation of CBP and decreasing binding affinity for CREB (17,18,27). How does one signal, such as elevated level of cytosolic Ca 2þ stimulate and inhibit expression of the same gene?…”

“…Elevated Ca 2þ levels can also enable calmodulin binding to other CaM kinases (15,16), which may exert contradictory effects. For example, although calmodulin-dependent kinase IV (CaMKIV) and CaMKIIα bind to the same site in calmodulin, they exert opposing effects, which can be explained by differences in phosphorylation (17,18). However, the mechanisms by which two kinases are regulated by a single stimulus remain to be studied.…”

Activation of the rat dopamine D2 receptor promoter by mitogen‐activated protein kinase and Ca2+/calmodulin‐dependent protein kinase II pathways

“…CaMKIV and PKA stimulate gene expression through phosphorylation of Ser133 of the cAMP responsive element binding protein (CREB) (Enslen et al 1994;Montminy 1997). CaMKII phosphorylates not only Ser133 but also Ser142 of CREB, thereby blocking its function (Mattews et al 1994). CaMKII also phosphorylates CCAAT/enhancer-binding protein b (C/EBPb) (Wegner et al 1992;Yano et al 1996), activating transcription factor-1 (ATF-1) (Shimomura et al 1996) and serum response factor (SRF) (Miranti et al 1995) and stimulates expression of atrial natriuretic factor (Ramirez et al 1997) and brain-derived neurotrophic factor (BDNF) (Takeuchi et al 2000).…”