Protein Phosphorylation and Cell Signaling Transduction

Protein phosphorylation-dephosphorylation has a role in the regulation of essentially all cellular functions. Thus, it is of interest that this process is involved in signaling transduction.

Nonetheless, the extent to which protein phosphorylation participates in signaling is truly remarkable. Almost every known signaling pathway eventually impinges on a protein kinase, or in some instances, a protein phosphatase.

The diversity of these enzymes is noteworthy, and it is of interest that many biotechnology companies are eyeing them as potentially important targets for drugs. Such drugs may have important therapeutic applications, and in any event, they certainly will be useful to investigators who study signaling transduction. Indeed, this already has been proven to be true.

Cyclic AMP Signaling Pathway

In skeletal muscle, the mechanism by which cAMP activates phosphorylase kinase involves its phosphorylation by a second protein kinase, the cAMP-dependent protein kinase, or protein kinase A (PKA).

PKA had many protein substrates other than phosphorylase kinase. These included other enzymes, for example, glycogen synthase, pyruvate kinase, the hormone-sensitive lipase, etc., as well as many nonenzymic proteins; among the latter were the transcription factor CREB, contractile proteins, secretory proteins, and others. It became clear that a broad spectrum of cellular processes is regulated by PKA, in keeping with an early prediction of Greengard and collaborators.

SAP Kinase (SAPK) Pathway AND p38 MAP Kinase (MAPK) Pathway

The p46 and p54 stress-activated protein kinase (SAPK) pathway is activated by tumor necrosis factor (TNF)-alpha, UV light, and protein synthesis inhibitors. Three members of a family, referred to as p38 MAPK, have also been cloned. Stimuli for the p38 MAPK pathway overlap those for the SAPK pathway and include lipopolysaccharides, interleukin (IL)-1, arsenite, and osmotic shock.

In common with the MAPK pathway, SAPK and p38 MAPK are activated by sequential phosphorylation pathways. The Rho family GTPases Rac1 and cdc42Hs are thought to play an important role upstream in the SAPK and p38 MAPK pathways. Candidates for coupling these GTPases to SAPK and p38 are the p21-activated kinases (PAKs). The three mammalian PAKs are 60- to 70-kDa serine/threonine kinases that are homologous to Saccharomyces cerevisiae Ste20 and are activated upon recruitment to activated Rac1/cdc42Hs.

A major role for the SAPK pathway is phosphorylation and activation of the transcription factor c-Jun, which participates in activator protein-1-mediated gene regulation. Amongst the p38 MAPK targets that have been identified are the MAPK-activated protein kinases (MAPKAPK-2 and -3) and the MAPK interacting protein kinase-1 and -2. In addition, p38 MAPK has been shown to phosphorylate and activate the activation transcription factor-2 and to cooperate with MAPK in the regulation of the serum response element by phosphorylation of the ternary complex factor.

References

1. Graves, J. D., & Krebs, E. G. (1999). Protein phosphorylation and signal transduction. Pharmacology & therapeutics, 82(2), 111-121.

Cell Signaling Transduction