Scaffold proteins and immune-cell signalling

Shaw, Andréy S.; Filbert, Erin L.

doi:10.1038/nri2473

Cited by 195 publications

(190 citation statements)

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“…A screen for candidates whose depletion resulted in nuclear accumulation of NFAT1 in resting cells yielded two well-known Drosophila scaffold proteins, Homer and Discs Large (4), known to affect Ca 2þ signaling upstream of NFAT (8). Homer2 and Homer3 also directly interact with NFAT (9).…”

mentioning

confidence: 99%

Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Sharma

Findlay²,

Bandukwala³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

253

230

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mentioning

confidence: 99%

Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Sharma

Findlay²,

Bandukwala³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

253

230

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“…Assembly of signaling components mediated by scaffolding proteins can enhance spatial coordination to the signaling target for an efficient feedback mechanism (51). Given the significance of the ILK-mediated membrane-cytoskeleton linkage associated with signaling pathways in many biological processes, such as cardiovascular development, identification of the signaling molecules that directly interact with ILK and/or its binding partners will be necessary to provide new insights into the coordinated molecular and signaling mechanisms in ILK-mediated integrin biology.…”

Section: Discussionmentioning

confidence: 99%

Biochemical, Proteomic, Structural, and Thermodynamic Characterizations of Integrin-linked Kinase (ILK)

Fukuda

Knight

Piszczek

et al. 2011

Journal of Biological Chemistry

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Integrin-linked kinase (ILK) is one of the few evolutionarily conserved focal adhesion proteins involved in diverse cell adhesion-dependent physiological and pathological responses. Despite more than a decade of studies and extensive literature, the kinase function of ILK is controversial. ILK contains a highly degraded kinase active site but it has been argued that ILK may be an unusual manganese (Mn)-dependent serine-threonine kinase that targets specific substrates such as glycogen synthase kinase-3␤ (GSK-3␤). In this study, we have tackled this issue by a systematic bottom-up biochemical, proteomic, structural, and thermodynamic analysis of ILK. We show that recombinant ILK from either bacteria or mammalian cells exhibits no kinase activity on GSK-3␤ in the presence of either Mn 2؉ or the conventional kinase co-factor Mg 2؉ . A comprehensive and unbiased whole cell-based kinase assay using entire mammalian CG-4 and C2C12 cell lysate did not identify any specific ILK substrates. High resolution crystallographic structure analysis further confirmed that the Mn-bound ILK adopts the same pseudo active site conformation as that of the Mg-bound ILK. More importantly, thermodynamic analysis revealed that the K220M mutation, previously thought to inactivate ILK by disrupting ATP binding, significantly impairs the structural integrity and stability of ILK, which provides a new basis for understanding how this mutation caused renal agenesis, a failure of fetal kidney development. Collectively, our data provide strong evidence that ILK lacks intrinsic kinase function. It is a bona fide pseudokinase that likely evolved from an ancestral catalytic counterpart to act as a distinct scaffold to mediate protein-protein interactions during focal adhesion assembly and many other cellular events.The adhesion of cells to the extracellular matrix (ECM) 3 is primarily mediated by heterodimeric integrin transmembrane receptors. Upon activation, the integrin extracellular domain adheres to the ECM by binding to numerous ligands such as fibronectin and fibrinogen. However, for cells to firmly adhere to the ECM, integrins must connect to the backbone of the cell, the actin cytoskeleton, via its cytoplasmic tails (CTs) (1-2). Such connection is mediated by the supramolecular focal adhesion (FAs) complex. The reassembly/disassembly of FAs can lead to dynamic cell adhesion processes such as cell migration and spreading, which are fundamental for a variety of physiological responses. Over the past decades, major effort has been made to search for proteins involved in FA assembly and regulation. Integrin-linked kinase (ILK) was discovered in 1996 as a binding partner of integrin ␤ CTs (3) and was found to critically regulate FAs (4). Genetic and genomic analyses have established that ILK is one of the few essential and evolutionarily conserved proteins coupling integrins to actin (5-7), and its dysregulation has been linked to major human diseases such as heart failure (8 -10) and cancer (11). ILK has a molecular mass of ϳ51 kDa containi...

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“…They also serve as platforms for assembling enzymes and their substrates, restraining the nonspecific access of enzymes to unwanted substrates and protecting from undesirable cellular effects [3]. Some scaffold proteins can have other functions, like coordination of the positive and negative feedback signals or protection of activated proteins from inactivation [1]. Interestingly, scaffold proteins may exhibit distinct functions under different physiological conditions [4].…”

Section: Introductionmentioning

confidence: 99%

“…Scaffold proteins typically do not posses any enzymatic or transcriptional activity, but they have the ability to assemble various combinations of multi-protein complexes, necessary for integration of signals and selective transmission of information from the surface receptors [1,2]. In most cases, scaffolds help to localize signaling molecules to specific parts of cell.…”

Section: Introductionmentioning

confidence: 99%

“…Scaffold proteins are defined as molecules that bind to at least two other signaling proteins [1]. Scaffold proteins typically do not posses any enzymatic or transcriptional activity, but they have the ability to assemble various combinations of multi-protein complexes, necessary for integration of signals and selective transmission of information from the surface receptors [1,2].…”

Section: Introductionmentioning

confidence: 99%

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NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Blonska¹,

Lin²

2010

Cell Res

171

201

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The NF-κB family of transcription factors plays a crucial role in cell activation, survival and proliferation. Its aberrant activity results in cancer, immunodeficiency or autoimmune disorders. Over the past two decades, tremendous progress has been made in our understanding of the signals that regulate NF-κB activation, especially how scaffold proteins link different receptors to the NF-κB-activating complex, the IκB kinase complex. The growing number of these scaffolds underscores the complexity of the signaling networks in different cell types. In this review, we discuss the role of scaffold molecules in signaling cascades induced by stimulation of antigen receptors, G-protein-coupled receptors and C-type Lectin receptors, resulting in NF-κB activation. Especially, we focus on the family of Caspase recruitment domain (CARD)-containing proteins known as CARMA and their function in activation of NF-κB, as well as the link of these scaffolds to the development of various neoplastic diseases through regulation of NF-κB.

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Scaffold proteins and immune-cell signalling

Cited by 195 publications

References 100 publications

Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Biochemical, Proteomic, Structural, and Thermodynamic Characterizations of Integrin-linked Kinase (ILK)

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

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