Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

Le, Lu Q.; Parada, Luis F.

doi:10.1038/sj.onc.1210261

Cited by 170 publications

(152 citation statements)

References 45 publications

(54 reference statements)

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“…The Ras GTPases interact with multiple pathways, including the Raf/Mek/Erk mitogen-activated protein kinase cascade, which regulates cellular growth and differentiation. 24 NF1 belongs to a class of developmental syndromes called RASopathies, which are caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase pathway. 25 …”

Section: Functions Of Neurofibrominmentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell-extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a "second hit" seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1 ؉/؊ genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. café-au-lait macules and multiple benign cutaneous neurofibromas, which, typically, are detectable in adulthood by simple visual inspection.NF1 can affect nearly every organ system, and the complications vary between individuals, even within a single family. The clinical diagnosis is based on the presence of two or more of the following findings: six or more café-au-lait macules with diameters Ͼ5 mm in prepubertal patients and Ͼ15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion, such as sphenoid wing dysplasia or pseudarthrosis; or a first-degree relative diagnosed as having NF1 according to the preceding criteria. 3 It has been suggested that a pathogenic mutation in the NF1 gene be added to the list of diagnostic criteria. 4 The most common complications of NF1 are included in the previously listed diagnostic criteria. Additional features include short stature, scoliosis, headache, speech disorders, attention deficit disorder and attention-deficit/ hyperactivity disorder, and learning disabilities. Rare complications, affecting Ͻ5% of patients, include epilepsy, hydrocephalus, cardiovascular problems, and dystrophic scoliosis. 5 The lifetime risk of malignant tumors arising from peripheral nerves is estimated to be 10% to 13%. 6 The pathoetiology of the complications in NF1 is, however, largely unknown. Genetic BackgroundNF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin. 7,8 The NF1 gene is located on chromosome band 17q11.2, spanning approximately 280 kb of genomic DNA, and is composed of 57 constitutive exons and 4 alternatively spliced exons (9a, 10a2, 23a, and 48a). 9 Howeve...

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Section: Functions Of Neurofibrominmentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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“…Mammalian proteins capable of functioning as GAPs for H-, K-, and N-Ras represent a large and divergent protein family and include p120GAP, neurofibromin (NF1), the GAP1 family, including GAP1 IP4BP , Ca 2+ -promoted Ras inactivator (CAPRI), Ras GTPase activating-like protein RASAL, as well as the SynGAP family (DAB2IP, nGAP, SynGAP). 14,[24][25][26][27][28][29][30] Some of those are expressed ubiquitously, while others show very restricted expression profiles, making it difficult to assign a member of the GAP family with Ras inactivation in a given cell/tissue. In addition, structural analysis indicated that NF1 and p120GAP bind Ras isoforms without any preference.…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…Different domain arrangements in GAPs to create differential protein-protein and proteinlipid interactions are probably key factors determining the GTP/GDP ratio bound to H−, K−, and N-Ras. 14,[24][25][26][27][28][29][30] Cell-and animal-based studies examining GAP activity, interaction partners, and expression profiles have provided further insights into Ras inactivation in normal and transformed cells. Mammalian proteins capable of functioning as GAPs for H-, K-, and N-Ras represent a large and divergent protein family and include p120GAP, neurofibromin (NF1), the GAP1 family, including GAP1 IP4BP , Ca 2+ -promoted Ras inactivator (CAPRI), Ras GTPase activating-like protein RASAL, as well as the SynGAP family (DAB2IP, nGAP, SynGAP).…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…[9][10][11] Yet, an increasing number of studies suggest that differential GAP expression patterns and Ras/GAP assembly must be involved in cellular transformation. NF1, which is a tumor suppressor only in neuronal and myeloid cells, [25][26][27][28] is probably the best example for the tissue-specific transforming potential of an individual member of the GAP protein family. CAPRI confers tumor suppressor activity in mammary epithelial cells, 31 and RASAL is downregulated in tumors from the brain, skin, bladder, head, and neck as well as multiple cell lines from the nasopharynx, breast, lung, liver, and esophagus.…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…In support of this hypothesis, the different domain arrangements in GAPs point at different functions and interactions. [24][25][26][27][28][29][30] …”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

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Differential Regulation of RasGAPs in Cancer

et al. 2011

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Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell-and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

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Neurofibromatosis Type I ( NF 1)

Viskochil

2009

Encyclopedia of Life Sciences

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Neurofibromatosis type I (NF1) is a common, autosomal dominant condition that manifests as multiple café‐au‐lait spots, peripheral nerve sheath tumours, optic nerve pathway tumours, orthopaedic abnormalities and learning disabilities. The gene for NF1 encodes neurofibromin, a RasGTPase activating protein (RasGAP) that activates the intrinsic GTPase of Ras and negatively regulates its role in signal transduction. As a tumour suppressor, inactivating mutations in NF1 lead to increased intracellular Ras signalling. Other components of the Ras‐MAP (mitogen‐activated protein) kinase pathway are now known to be involved in other genetic conditions including Noonan syndrome, Costello syndrome, Cardio‐facial‐cutaneous syndrome and Legius syndrome. NF1 is a neurocutaneous disorder that is a paradigm for many principles in the practice of medical genetics: variable clinical expressivity, penetrance, pleiotropy, age‐dependent clinical expression and mosaicism. The development of inhibitors of the Ras‐MAPK pathway, and other Ras‐connected pathways, opens new avenues of therapeutic intervention for myriad complications of this disorder. Key concepts Tumour suppressor : The NF1 gene loosely fits the paradigm of the “two‐hit” model of tumour suppressor in that somatic inactivation of a haploinsufficient gene in a subset of cells leads to tumour development. Variability of clinical expressivity : NF1 demonstrates multiple phenotypes, even in the same family where all affected individuals have the identical gene mutation. Age‐related penetrance : The clinical manifestations of NF1 arise at different ages and the condition is fully penetrant in adults. Genomic structure : The NF1 gene is traditional in its gene structure, yet there are unique features including embedded genes transcribed in the opposite orientation and multiple disease‐causing translocation breakpoints. Value of diagnostic criteria : NF1 is one of the few genetic conditions that can be diagnosed by the application of seven diagnostic criteria. Mosaicism : NF1 has a high sporadic incidence, and somatic mutations occurring in early pregnancy can lead to a mosaic clinical presentation evident by skin manifestations. Positional cloning : The NF1 gene was identified by application of genetic and physical mapping techniques. Animal models : Animal models, particularly the conditional mice, have been instrumental in furthering our understanding of this condition. Integration of kinase pathways : The Ras‐MAPK pathway is integrated in the intracellular network of signalling that includes growth factor receptors at the cell membrane. Pathophysiology : The understanding of the biochemical pathway and processes leading to tumour formation have led to the design and application of specific therapeutics that would not otherwise have been considered in the treatment of NF1.

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Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

Cited by 170 publications

References 45 publications

The Pathoetiology of Neurofibromatosis 1

The Pathoetiology of Neurofibromatosis 1

Differential Regulation of RasGAPs in Cancer

Neurofibromatosis Type I ( NF 1)

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