Protein phosphatases regulation

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

Shenolikar, S. Protein phosphatase regulation by endogenous inhibitors. Cancer Biol. 6 219-227,1995. 

The last part of this account will be devoted to protein kinases and protein phosphatases and some recent results we have obtained for them. Protein kinases and phosphatases are signaling biomolecules that control the level of phosphorylation and dephosphorylation of tyrosine, serine or threonine residues in other proteins, and by this means regulate a variety of fundamental cellular processes including cell growth and proliferation, cell cycle and cytoskeletal integrity. 

FIGURE 15.2 Enzymes regulated by covalent modification are called interconvertible enzymes. The enzymes protein kinase and protein phosphatase, in the example shown here) catalyzing the conversion of the interconvertible enzyme between its two forms are called converter enzymes. In this example, the free enzyme form is catalytically active, whereas the phosphoryl-enzyme form represents an inactive state. The —OH on the interconvertible enzyme represents an —OH group on a specific amino acid side chain in the protein (for example, a particular Ser residue) capable of accepting the phosphoryl group. 

Protein phosphatases are classified according to their activity toward phospho-amino acids they act on (Fig. 1). Nomenclature is independent of regulation simply because stimuli were unknown. Protein phosphatases hydrolyzing O-phospho-monoesters are currently subdivided into two major classes (i) phosphatases acting on phosphoserine (pSer) and phosphothreonine (pThr), and (ii) the second class... 

In vivo, protein phosphatases are tightly regulated by diverse mechanisms including... 

Numerous protein phosphatases are targeted to their substrates and regulators through the interaction with specific scaffolding proteins. Some of these anchoring proteins bind both, kinases and phosphatases. This applies to ser/thr protein phosphatases as well as to tyrosine phosphatases. 

Many proteins can be phosphorylated at multiple sites or are subject to regulation both by phosphorylation-dephosphorylation and by the binding of allosteric ligands. Phosphorylation-dephosphorylation at any one site can be catalyzed by multiple protein kinases or protein phosphatases. Many protein kinases and most protein phosphatases act on more than one protein and are themselves interconverted between active and inactive forms by the binding of second messengers or by covalent modification by phosphorylation-dephosphorylation. 

Calcineurin Cytosol A calmodulin-regulated protein phosphatase. May play important roles in cardiac hypertrophy and in regulating amounts of slow and fast twitch muscles. 

Figure 2. Regulators of the Cdc2 protein kinase. Schematic illustration of the regulators of Cdc2 kinase activity. Proteins that are circled indicate proteins that have been identified in higher eukaryotes only the squared proteins have been identified exclusively in the yeast systems. The remaining proteins have been identified in both higher and lower eukaryotes. Protein phosphatases are indicated by p tase.

Other phosphatases have also been identified and may be implicated in mitotic and meiotic germ cell functions. For example, INH was originally isolated from a Xenopus oocyte cell free system as an inhibitor of pre-MPF activity (Cyert and Kirschner, 1988). INH encodes a protein phosphatase 2Athat negatively regulates MPF activity by dephosphory-lating Cdc2 on thr-161 (Lee et al., 1991 Solomon et al., 1990). 

Clarke, P. R., Hoffman, I., Draetta, G., and Karsenti, E. (1993). Dephosphorylation of cdc25-C by a type-2A protein phosphatase specific regulation during the cell cycle in Xenopus egg extracts. Mol. Biol. Cell 4 397—411. 

Kinoshita, N., Yamano, H., Niwa, H Yoshida, T., and Yanagida, M. (1993). Negative regulation of mitosis by the fission yeast protein phosphatase ppa2. Genes Dev. 7 1059-1071. 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

Yan, Z., Hsieh-Wilson, L., Feng, J. et al. Protein phosphatase 1 modulation of neostriatal AMPA channels regulation by DARPP-32 and spinophilin. Nat. Neurosci. 2 13, 1999. 

When glucagon levels fall, cAMP phosphodiesterase destroys the accumulated cAMP, and specific protein phosphatases remove the phosphate from the phosphoproteins. These phosphatases themselves are often regulated by phosphorylation—yes, there are phosphatase kinases and phosphatase phosphatases. It s really easy to lose it here, but the key factor is that increased glucagon levels lead to increased protein phosphorylation, and decreased glucagon levels lead to decreased protein phosphorylation. 

Sharma, R. and Wang, J. H. Differential regulation of bovine brain calmodulin-dependent cyclic nucleotide phosphodiesterase isozzymesdby cyclic AMP-dependent protein kinase and calmodulin-dependent protein phosphatase. Proc. Natl Acad. Sci. U.S.A. 82 2603-2607,1986. 

Regulation of protein phosphorylation involves a protein kinase, a protein phosphatase and a substrate protein 391... 

Protein phosphatase 1 is regulated by protein phosphatase inhibitor proteins 401... 

Regulation of protein phosphorylation involves a protein kinase, a protein phosphatase and a substrate protein. These components interact according to the scheme shown in Figure 23-1. A substrate protein is converted from the dephospho form to the phospho form by a protein kinase, and the phospho form is converted back to the dephospho form by a protein phosphatase [1]. 

Cdc, cell division cycle DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32kDa MAPK, mitogen-activated protein kinase NIPP1, nuclear inhibitor of PP1 PP, protein phosphatase Vffl, vaccinia virus. 

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