Dataset Information

Identification of mitogen-activated protein kinase docking sites in enzymes that metabolize phosphatidylinositols and inositol phosphates.

ABSTRACT: Reversible interactions between the components of cellular signaling pathways allow for the formation and dissociation of multimolecular complexes with spatial and temporal resolution and, thus, are an important means of integrating multiple signals into a coordinated cellular response. Several mechanisms that underlie these interactions have been identified, including the recognition of specific docking sites, termed a D-domain and FXFP motif, on proteins that bind mitogen-activated protein kinases (MAPKs). We recently found that phosphatidylinositol-specific phospholipase C-gamma1 (PLC-gamma1) directly binds to extracellular signal-regulated kinase 2 (ERK2), a MAPK, via a D-domain-dependent mechanism. In addition, we identified D-domain sequences in several other PLC isozymes. In the present studies we sought to determine whether MAPK docking sequences could be recognized in other enzymes that metabolize phosphatidylinositols (PIs), as well as in enzymes that metabolize inositol phosphates (IPs).We found that several, but not all, of these enzymes contain identifiable D-domain sequences. Further, we found a high degree of conservation of these sequences and their location in human and mouse proteins; notable exceptions were PI 3-kinase C2-gamma, PI 4-kinase type IIbeta, and inositol polyphosphate 1-phosphatase.The results indicate that there may be extensive crosstalk between MAPK signaling and signaling pathways that are regulated by cellular levels of PIs or IPs.

SUBMITTER: Caldwell KK

PROVIDER: S-EPMC1379644 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Identification of mitogen-activated protein kinase docking sites in enzymes that metabolize phosphatidylinositols and inositol phosphates.

Caldwell Kevin K KK Sosa Marcos M Buckley Colin T CT

Cell communication and signaling : CCS 20060130

<h4>Background</h4>Reversible interactions between the components of cellular signaling pathways allow for the formation and dissociation of multimolecular complexes with spatial and temporal resolution and, thus, are an important means of integrating multiple signals into a coordinated cellular response. Several mechanisms that underlie these interactions have been identified, including the recognition of specific docking sites, termed a D-domain and FXFP motif, on proteins that bind mitogen-ac ...[more]

PMID: 16445858

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Project description:Mitogen-activated protein kinases (MAPK) are important regulatory units in cells and they take part in the regulation of many cellular functions such as cell division, differentiation or apoptosis. All MAPKs have a shallow docking groove that interacts with linear binding motifs of their substrate proteins and their regulatory proteins such as kinases, phosphatases, scaffolds. Inhibition of these protein-protein interactions may reduce or abolish the activity of the targeted kinase. Based on the wide range of their biological activity, this kind of inhibition can be useful in the treatment of many disorders like tumors, inflammation or undesired cell apoptosis. In this study a linear binding motif from the RHDF1 protein-a 15 amino acids long peptide-was selected for optimization to increase its cellular uptake but retaining its low micromolar binding affinity. First, we synthesized an octaarginine conjugate that showed efficient cellular uptake. Next, we set out to reduce the size of this construct. We were able to decrease the length of the original peptide, and to increase its cellular uptake with specific chemical modifications. These new constructs bound better to ERK2 and p38 kinases than the original peptide and they showed markedly increased cellular uptake. The new octaarginine conjugate and one of the minimized bicyclic derivatives could inhibit the phosphorylation of intracellular ERK or p38. However, the modulation of MAPK phosphorylation levels by these cell-penetrating peptides were complex, despite that in biochemical assays they all inhibited MAPK-substrate binding as well as phosphorylation. The optimized peptides depending on the applied concentration caused an expected decrease, but also some unexpected increase in MAPK phosphorylation patterns in the cell. This possibly reflects the complexity of MAPK docking groove mediated protein-protein interactions including bone fide MAPK clients such activator kinases, deactivating phosphatases or regulatory scaffolds. Thus, our findings with optimized cell-penetrating "inhibitory" peptides highlight the opportunities but also the pitfalls of docking peptide based MAPK activity regulation and call for a better quantitative understanding of MAPK mediated protein-protein interactions in cells.

Dataset Information

Identification of mitogen-activated protein kinase docking sites in enzymes that metabolize phosphatidylinositols and inositol phosphates.

Publications

Identification of mitogen-activated protein kinase docking sites in enzymes that metabolize phosphatidylinositols and inositol phosphates.

Similar Datasets

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