Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules

Xu, Hua-mei; Gutmann, David H.

doi:10.1016/s0006-8993(97)00328-4

Cited by 64 publications

(40 citation statements)

References 17 publications

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“…K1468T was the only mutant not tested in the context of a full-length transgene. K1468 corresponds to human NF1 K1423, implicated as important for GAP activity and microtubule association of neurofibromin ( Poullet et al 1994;Xu and Gutmann 1997). All proteins were expressed at similar levels when driven by Act5C-GAL4 (Fig.…”

Section: Neuronal Expression Of a Functional Nf1grd Is Necessary And mentioning

confidence: 99%

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

Walker¹,

Tchoudakova²,

McKenney³

et al. 2006

Genes Dev.

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Neurofibromatosis type 1 (NF1) is among the most common genetic disorders of humans and is caused by loss of neurofibromin, a large and highly conserved protein whose only known function is to serve as a GTPase-Activating Protein (GAP) for Ras. However, most Drosophila NF1 mutant phenotypes, including an overall growth deficiency, are not readily modified by manipulating Ras signaling strength, but are rescued by increasing signaling through the cAMP-dependent protein kinase A pathway. This has led to suggestions that NF1 has distinct Ras-and cAMP-related functions. Here we report that the Drosophila NF1 growth defect reflects a non-cell-autonomous requirement for NF1 in larval neurons that express the R-Ras ortholog Ras2, that NF1 is a GAP for Ras1 and Ras2, and that a functional NF1-GAP catalytic domain is both necessary and sufficient for rescue. Moreover, a Drosophila p120RasGAP ortholog, when expressed in the appropriate cells, can substitute for NF1 in growth regulation. Our results show that loss of NF1 can give rise to non-cell-autonomous developmental defects, implicate aberrant Ras-mediated signaling in larval neurons as the primary cause of the NF1 growth deficiency, and argue against the notion that neurofibromin has separable Ras-and cAMP-related functions.[Keywords: Neurofibromatosis type 1; organismal growth control; non-cell autonomy; Ras signal transduction; Drosophila melanogaster]Supplemental material is available at http://www.genesdev.org. Neurofibromatosis type 1 (NF1, OMIM 162200) is a common genetic disorder, affecting two to three per 10,000 live births worldwide (Huson and Hughes 1994). NF1 patients are predisposed toward developing a variety of defects, the most characteristic of which include areas of abnormal skin pigmentation and benign tumors associated with peripheral nerves, termed neurofibromas. Less universal but more serious symptoms also include malignant peripheral nerve sheath tumors, other malignancies, and learning disabilities. Developmental abnormalities, such as specific skeletal defects, macrocephaly, and short stature, are also associated with NF1 (Huson and Hughes 1994). The >2800-amino-acid NF1 protein, termed neurofibromin, includes a segment related to the catalytic domains of Ras-specific GTPase-Activating Proteins (GAPs), and ample evidence supports the notion that the ability of neurofibromin to inactivate Ras plays a critical role in the development of NF1-associated tumors (Cichowski and Jacks 2001). The GAP-related domain (GRD) constitutes only ∼15% of neurofibromin, however, and it is less clear whether Ras signaling defects are also the immediate cause of other disease symptoms.A Drosophila melanogaster NF1 ortholog predicts a protein that is ∼60% identical to human neurofibromin over its entire length. We previously reported that Drosophila NF1-null mutants are viable, fertile, and normally patterned, but display a 15%-20% reduction in linear dimensions during all stages of post-embryonic

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Section: Neuronal Expression Of a Functional Nf1grd Is Necessary And mentioning

confidence: 99%

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

Walker¹,

Tchoudakova²,

McKenney³

et al. 2006

Genes Dev.

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“…These learning deficits may also relate to the ability of NF1 to associate with microtubules, which are expressed at high level in axonal and dendritic processes of neurons. Gregory et al (1993) and Xu and Gutmann (1997) have shown that the region of NF1 that is critical for this interaction resides within the Ras-GRD. Although microtubules may be important for neuronal connection and neurite outgrowth, the exact function of NF1 relative to microtubules is currently unknown.…”

Section: Biology Of Neurofibrominmentioning

confidence: 99%

Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

2007

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“…Neurofibromin shows a Ras GTPase-activating activity (28,29) and is involved by means of Ras signal transduction in the regulation of growth (21,30). In addition, it is found to be associated with the cytoskeleton (31). NF1-deficient cells exhibit morphological changes, as demonstrated for Nf1 Ϫ/Ϫ Schwann cells (30) or cells from Drosophila homozygous for null mutations of an NF1 homologue (32).…”

mentioning

confidence: 99%

Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro

Kemkemer

Schrank

Vogel

et al. 2002

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

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In human diseases related to tumor-suppressor genes, it is suggested that only the complete loss of the protein results in specific symptoms such as tumor formation, whereas simple reduction of protein quantity to 50%, called haploinsufficiency, essentially does not affect cellular behavior. Here, we demonstrate that haploinsufficiency of the tumorsuppressor gene neurofibromatosis type 1 (NF1) results in an increased variation of dendrite formation in cultured NF1 melanocytes. These morphological differences between NF1 and control melanocytes can be described by a mathematical model in which the cell is considered to be a self-organized automaton. The model describes the adjustment of the cells to a set point and includes a noise term that allows for stochastic processes. It describes the experimental data of control and NF1 melanocytes. In the cells haploinsufficient for NF1 we found an altered signal-to-noise ratio detectable as increased variation in dendrite formation in two of three investigated morphological parameters. We also suggest that in vivo NF1 haploinsufficiency results in an increased noise in cellular regulation and that this effect of haploinsufficiency may be found also in other tumor suppressors.

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Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules

Cited by 64 publications

References 17 publications

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro

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