Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

Welti, Stefan; Kühn, Sonja; D’Angelo, I.; Brügger, Britta; Kaufmann, Dieter; Scheffzek, Klaus

doi:10.1002/humu.21405

Cited by 28 publications

(29 citation statements)

References 39 publications

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“…The precise nature of such a ligand is currently unclear. The integrity of the inter domain linker does not seem to be essential for the stability of the interface between the two domains, since a mutation essentially duplicating the linker does not affect the overall structure of the Sec14‐PH module or the relative position of the two domains [105]. While glycreophospholipid binding of the Sec14‐component is well established [101] and the Sec14‐PH module binds phosphatidylinositol phosphates with moderate specificity in overlay assays [100], the function of the module and particularly of its PH portion is currently unclear.…”

Section: Ph‐like Modules In Different Molecular Contexts and Functionsmentioning

confidence: 99%

Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

2012

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a b s t r a c tThe initial reports on pleckstrin homology (PH) domains almost 20 years ago described them as sequence feature of proteins involved in signal transduction processes. Investigated at first along the phospholipid binding properties of a small subset of PH representatives, the PH fold turned out to appear as mediator of phosphotyrosine and polyproline peptide binding to other signaling proteins. While phospholipid binding now seems rather the exception among PH-like domains, protein-protein interactions established as more and more important feature of these modules. In this review we focus on the PH superfold as a versatile protein-protein interaction platform and its three-dimensional integration in an increasing number of available multidomain structures.

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Section: Ph‐like Modules In Different Molecular Contexts and Functionsmentioning

confidence: 99%

Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

2012

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“…Neurofibromin also contains a bipartite domain C-terminal to the GRD that contains both a segment homologous to the yeast Sec14p protein and a pleckstrin homology domain [34]. Although the function of this Sec14p homology domain is incompletely understood, it can specifically bind glycerophospholipids [194] and structural studies predict that mutations in this domain will interfere with as yet undefined protein-protein interactions [195]. A focal adhesion kinase (FAK)-interacting domain, which allows neurofibromin to modulate substrate adherence, is additionally present at the C-terminal end of neurofibromin [97].…”

Section: Neurofibromas and Mpnstsmentioning

confidence: 99%

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Carroll

2011

Acta Neuropathol

107

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Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.

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“…Several additional pathways are regulated additionally by neurofibromin, such as mTOR and Akt [Dasgupta et al, 2005b;Lee et al, 2007;Banerjee et al, 2011]. The central GRD is flanked by a lipid-binding Sec14p-like domain (NF1-Sec) and a pleckstrin homology-like domain (NF1-PH) adjacent to and interacting with the NF1-Sec portion [D'Angelo et al, 2006;Welti et al, 2008Welti et al, , 2011. In addition, a physical interaction between neurofibromin and focal adhesion kinase (FAK) has been reported, suggesting an involvement of neurofibromin in cell adhesion [Kweh et al, 2009].…”

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confidence: 99%

Partial Blindness to Submicron Topography in <b><i>NF1</i></b> Haploinsufficient Cultured Fibroblasts Indicates a New Function of Neurofibromin in Regulation of Mechanosensoric

Kaufmann

Hoesch

Su³

et al. 2012

Mol Syndromol

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Cells sense physical properties of their extracellular environment and translate them into biochemical signals. In this study, cell responses to surfaces with submicron topographies were investigated in cultured human NF1 haploinsufficient fibroblasts. Age-matched fibroblasts from 8 patients with neurofibromatosis type 1 (NF1^+/–) and 9 controls (NF1^+/+) were cultured on surfaces with grooves of 200 nm height and lateral distance of 2 µm. As cellular response indicator, the mean cell orientation along microstructured grooves was systematically examined. The tested NF1 haploinsufficient fibroblasts were significantly less affected by the topography than those from healthy donors. Incubation of the NF1^+/– fibroblasts with the farnesyltransferase inhibitor FTI-277 and other inhibitors of the neurofibromin pathway ameliorates significantly the cell orientation. These data indicate that NF1 haploinsufficiency results in an altered response to specific surface topography in fibroblasts. We suggest a new function of neurofibromin in the sensoric mechanism to topographies and a partial mechanosensoric blindness by NF1 haploinsufficiency.

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Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

Cited by 28 publications

References 39 publications

Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Partial Blindness to Submicron Topography in <b><i>NF1</i></b> Haploinsufficient Cultured Fibroblasts Indicates a New Function of Neurofibromin in Regulation of Mechanosensoric

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