Complex Formation between S100B Protein and the p90 Ribosomal S6 Kinase (RSK) in Malignant Melanoma Is Calcium-dependent and Inhibits Extracellular Signal-regulated Kinase (ERK)-mediated Phosphorylation of RSK

Hartman, Kira G.; Vítolo, Michele; Pierce, Adam D.; Fox, Jennifer M.; Shapiro, Paul; Martin, Stuart S.; Wilder, Paul T.; Weber, David J.

doi:10.1074/jbc.m114.561613

Cited by 27 publications

(36 citation statements)

References 65 publications

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“…As is typical for S100 proteins, the effects of S100B expression on melanoma cell growth are not limited to a single pathway. S100B binding to the p90 ribosomal S6 kinase (RSK) blocks ERK-dependent phosphorylation and results in cytoplasmic sequestration of RSK 124 . However, it is not known how the shift in the subcellular distribution of RSK affects cell growth.…”

Section: S100 Signalling In Cancer Biologymentioning

confidence: 99%

S100 proteins in cancer

2015

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In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.

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Section: S100 Signalling In Cancer Biologymentioning

confidence: 99%

S100 proteins in cancer

2015

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“…They are generally considered as relatively low specificity proteins, with dozens of interaction partners, among them they are unable to maintain a high selectivity [15]. In this study we determined the interaction profile of the full human S100 family (termed here as the S100ome) against a set of diverse known S100 partners (and some of their paralogs) systematically, including kinases such as RSK1 [16] and its paralogs MK2 and MNK1; cytoskeletal elements such as CapZ [17] (commonly known as TRTK12), NMIIA [18], ezrin [19], FOR20 and its paralog FOP [20]; membrane proteins such as NCX1 [15] and TRPM4 [21]; and other signaling proteins such as the tumor suppressor p53 [22][23][24], SIP [15] and MDM4 [23].…”

Section: Introductionmentioning

confidence: 99%

High throughput competitive fluorescence polarization assay reveals functional redundancy in the S100 protein family

Simon

Gógl

Ecsédi

et al. 2019

Preprint

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The calcium-binding, vertebrate-specific S100 protein family consists of 20 paralogs in humans (referred as the S100ome), with several clinically important members. To assess their interactome, high-throughput, systematic analysis is indispensable, which allows one to get not only qualitative but quantitative insight into their protein-protein interactions (PPIs). We have chosen an unbiased assay, fluorescence polarization (FP) that revealed a partial functional redundancy when the complete S100ome (n=20) was tested against numerous model partners (n=13). Based on their specificity, the S100ome can be grouped into two distinct classes: promiscuous and orphan. In the first group, members bound to several ligands (>4-5) with comparable high affinity, while in the second one, the paralogs bound only one partner weakly, or no ligand was identified (orphan). Our results demonstrate that in vitro FP assays are highly suitable for quantitative ligand binding studies of selected protein families. Moreover, we provide evidence that PPI-based phenotypic characterization can complement the information obtained from the sequence-based phylogenetic analysis of the S100ome, an evolutionary young protein family. Author summaryFunctional similarity among a protein family can be essential in order to understand proteomic data, to find biomarkers, or in inhibitor design. Proteins with similar functions can compensate the loss-offunction of the others, their expression can co-vary under pathological conditions, and simultaneous targeting can lead to better results in the clinics. To investigate this property one can use sequencebased approaches. However, this path can be difficult. In the case of the vertebrate specific, evolutionary young, S100 family, phylogenetic approaches lead to ambiguous results. To overcome this problem, we applied a high-throughput biochemical approach to experimentally measure the binding affinities of a large number of S100 interactions. We performed unbiased fluorescence polarization assay, involving the complete human S100ome (20 paralogs) and 13 known interaction partners. We used this measured 20x13 (260) protein-protein interaction array to reveal the functional relationships within the family. Our work provide a general framework for studies focusing on phenotype-based domain classification.

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“…MAPK pathway contain a functional class 1 PBM (Thomas et al, 2005). RSK has an emerging role in multiple cancer types such as glioblastoma or melanoma (Sulzmaier et al, 2016) (Hartman et al, 2014). Upon mitogenic stimuli, a series of phosphorylation events leads to the activation of the MAP kinase ERK1/2 (Pouysségur et al, 2002).…”

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Rewiring of RSK-PDZ interactions by linear motif phosphorylation

Gógl

Durbesson

Jané

et al. 2018

Preprint

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Protein phosphorylation is a key regulator of protein-protein interactions. How does the interactome of a protein change during extracellular stimulations? While many individual examples of phosphorylation-regulated interactions were described previously, studies addressing the interactome changes induced by a particular phosphorylation event remain scarce. Here, we try to answer this question, by focusing on interactions between a phosphorylable PDZ-binding linear motif and the entire complement of human PDZ domains. Using a combination of in vitro quantitative techniques and cell-based approaches, we demonstrate that the activation of the mitotic effector kinase RSK1 causes dramatic changes in its connectivity with PDZ domain containing proteins. These changes consist of modulations of the binding affinity of numerous interactions, rather than on/off switching of a few interactions. Our results highlight the previously unappreciated role of phosphorylation in the complex and subtle rewiring of large numbers of protein-protein interactions.

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Complex Formation between S100B Protein and the p90 Ribosomal S6 Kinase (RSK) in Malignant Melanoma Is Calcium-dependent and Inhibits Extracellular Signal-regulated Kinase (ERK)-mediated Phosphorylation of RSK

Cited by 27 publications

References 65 publications

S100 proteins in cancer

S100 proteins in cancer

High throughput competitive fluorescence polarization assay reveals functional redundancy in the S100 protein family

Rewiring of RSK-PDZ interactions by linear motif phosphorylation

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