Multiple pathway signal tran sduction by the cAMP‐dependent protein kinase

Abstract

Since its discovery a quarter century ago, the cAMP-dependent protein kinase has been a central model for study of the mode of transduction of second messenger signals; more than 300 protein kinases are now known to play keys roles in cellular control. Multiple cellular events are initiated by the activation of the cAMP-dependent protein kinase and correlated with these events has been the identification of a broad spectrum of protein substrates. From model substrates and inhibitors an excellent understanding has been obtained of the "optimum" sequence for protein phosphorylation by the cAMP-dependent protein kinases, and now, from pioneering crystal structure studies, we are beginning to understand exactly how an optimum substrate can interact with and be efficiently phosphorylated by the kinase. The next important step is for us to understand the full sequence of events that occurs within the cell upon activation of the protein kinase, and it is abundantly evident that this is indeed a complex process. It is not sufficient to simply know which proteins are phosphorylated but it is critical that we understand the dynamics of the events surrounding the phosphorylation of multiple proteins, what factors dictate those dynamics, and what might happen when the sequence of events is perturbed. This review focuses on the first simple question that must be addressed, namely, how might proteins vary as substrates for the cAMP-dependent protein kinase and what ramifications might such variations have for the consequential events within the cell?

Cholera toxin induces malignant glioma cell differentiation via the PKA/CREB pathway

“…PKA signaling has been reported to play important roles in multiple physiological processes, including growth, differentiation, gene regulation, and apoptosis (37). Disruption of the PKA catalytic subunit causes destabilization of the diploid cell cycle, and the cells start meiosis under conditions repressive for wild-type meiosis (38).…”

Multiplicity of the β Form of the cAMP-dependent Protein Kinase Inhibitor Protein Generated by Post-translational Modification and Alternate Translational Initiation

“…Much, however, remains to be determined about the physiological events of PKA-dependent phosphorylation. With the presence of multiple protein substrates in a single cell, there is a need for not only each substrate to be phosphorylated in response to a cAMP signal, but also for there to be some preference in the order of their phosphorylation and by this means to orchestrate the integration of the cellular response (38). Possibly the existence of multiple catalytic species contributes to such events.…”

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

“…As previously reported (Dormond et al, 2002), we found that EP2 and EP4 receptors were expressed in HUVECs and that EP4 was more abound than EP2 (data not shown), suggesting that cAMP may be involved in PGE2-mediated regulation of angiogenesis. The major target molecule of cAMP is PKA, which mediates its effects through phosphorylation of specific substrates (Walsh et al, 1994;Schwartz, 2001). It has also been shown that cAMP can activate the PI3K/Akt pathway (Li et al, 2000), which is involved in the angiogenic process (Walsh and Van Patten, 1994).…”

“…The major target molecule of cAMP is PKA, which mediates its effects through phosphorylation of specific substrates (Walsh et al, 1994;Schwartz, 2001). It has also been shown that cAMP can activate the PI3K/Akt pathway (Li et al, 2000), which is involved in the angiogenic process (Walsh and Van Patten, 1994). To test whether the angiogenic effect of PGE2 on endothelial cell migration, proliferation, and tube formation would be regulated by the PKA inhibitor PKI and the PI3K inhibitor wortmannin, HUVECs were treated with PGE2 following pretreatment with PKI or wortmannin for 30 min.…”

“…Since activation of Akt increases NO production by phosphorylating Ser 1177 of eNOS (Walsh and Van Patten, 1994), which is an important factor in regulating angiogenesis, we determined whether PGE 2 regulates both phosphorylation of Akt and eNOS using specific antibodies against phosphoAkt (Ser473) and phospho-eNOS (Ser1177) . Western blot HUVECs were cultured on a layer of Matrigel with or without PGE2 for 24 h. Tube formation was observed using an inverted phase contrast microscope, and images were captured with a video graphic system.…”