like Noonan syndrome, all of these cancers are associated with RAS signaling pathway mutations. (medscape.com)
NS is caused by mutations in PTPN11 (12q24.13) seen in 50% of cases, SOS1 (2p22.1) in 15%, RAF1 (3p25.2), RIT1 (1q22) and LZTR1 (22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. (orpha.net)
[3] [1] Noonan syndrome is a type of RASopathy , the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. (handwiki.org)
One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. (niepokorny.org)
KRAS4
A study by Cessans et al comparing growth patterns in patients with Noonan syndrome based on genotype found that at birth, patients with PTPN11 mutations tended to be shorter and thinner than were those with mutations in SOS1 , KRAS , or Noonan syndrome with multiple lentigines-associated PTPN11 (NSML- PTPN11 ). (medscape.com)
in a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. (unifesp.br)
Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. (niepokorny.org)
observed in a KRASG12C-mutated cancer cell line, which highlights the potential for combination therapy between a direct KRAS and a SOS1 inhibitor. (niepokorny.org)
Mitogen-activa2
M-Ras also weakly stimulates the mitogen-activated protein kinase (MAPK) activity and ERK2 activity, but modestly stimulates trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF- kB/Rel. (wikipedia.org)
Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. (univ-paris5.fr)
RAF11
Approximately 50% of patients have gene mutations in PTPN11 , with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. (medscape.com)
MAPK7
M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation. (wikipedia.org)
Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. (unifesp.br)
To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. (unifesp.br)
This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects. (unifesp.br)
Genetic screening revealed three signalling pathways, EGFR-Ras-MAPK, Notch and Wnt 1 , that are critical to the fate determination of the 6 vulval precursor cells (VPCs), P(3-8)p. (hideyuki-ts.com)
Figure 2.1 gives an overview of the pathways by which EGF-Ras-MAPK signalling leads to the 1 \(^\circ\) fate in P6.p and 2 \(^\circ\) fate in flanking P5.p and P7.p cells. (hideyuki-ts.com)
Downstram of the LET-23 (EGFR) RTK, a canocical Ras-MAPK pathway transduces the signal into the nucleus. (hideyuki-ts.com)
RASopathy2
FH, PH and RAS Kit analyzes 11, 11 and 30 genes and covers Familial Hypercholesterolemia (FH), Pulmonary Hypertension (PH) and RASopathy (RAS) related disorders, respectively. (medicover-genetics.com)
Methods 424 fetal samples, sent in for prenatal rasopathy testing in 2011-2016, were collected. (bmj.com)
Genes3
The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. (medscape.com)
however, only two disease-causing genes, SOS1 and REST , inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. (nature.com)
16 Among these loci, "son of sevenless homologue 1" ( SOS1 , OMIM 182530) and "RE1 silencing transcription factor" ( REST , OMIM 600571), which are HGF-related pathogenic genes, have been identified as associated with GINGF1 and GINGF5, respectively. (nature.com)
Proteins14
M-Ras is involved in many biological processes by activating a wide variety of proteins. (wikipedia.org)
Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders. (wikipedia.org)
For instance, the Ras-related proteins appear to be overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin, and breast, as well as in lymphomas. (wikipedia.org)
Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. (biomedcentral.com)
We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. (biomedcentral.com)
Proteins in cells with or without DN R-Ras expression were differentially labeled with SILAC and mass spectrometry was used to identify phosphoproteins and determine their relative quantities in the presence and absence of DN R-Ras. (biomedcentral.com)
R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion. (biomedcentral.com)
Mutations of the NF1 gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. (biomedcentral.com)
loss of neurofibromin could cause these Ras proteins to become persistently active, leading to the development of cancer. (biomedcentral.com)
We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. (biomedcentral.com)
Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. (biomedcentral.com)
We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. (biomedcentral.com)
Inhibition of R-Ras/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior. (biomedcentral.com)
The tumor suppressor DiRas3 forms a complex with H-Ras and C-RAF proteins and regulates localization, dimerization, and kinase activity of C-RAF. (univ-paris5.fr)
Pathways1
ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. (nature.com)
SOS21
The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12CCSOS1, SOS1, and SOS2. (niepokorny.org)
TC211
M-Ras is a member of the small GTPase superfamily under the Ras family, which also includes Rap1, Rap2, R-Ras, and R-Ras2 (TC21). (wikipedia.org)
Inhibition6
Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. (biomedcentral.com)
However, DN R-Ras inhibition impaired migration and invasion but not survival. (biomedcentral.com)
Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. (biomedcentral.com)
Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. (biomedcentral.com)
Indeed, covalent KRASG12C inhibitors are known to require GDP-bound inactive KRASG12C for binding, and potential combination therapies by upstream inhibition of RAS activation (e.g., by inhibition of receptor tyrosine kinase or RASGEF activity) have been discussed (11C13). (niepokorny.org)
Together, the data presented here indicate that inhibition of GEFs DprE1-IN-2 may represent a viable approach for targeting RAS-driven tumors. (niepokorny.org)
Inhibitor1
Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). (biomedcentral.com)
Interacts1
F1 interacts with SOS1 via a C interaction with Phe890 in its new Phe-out position and forms two hydrogen bonds to Tyr884 and Asp887 (Fig. 1= 4). (niepokorny.org)
MRAS1
Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. (wikipedia.org)
SHOC21
In addition, it is reported that M-Ras forms a complex with SCRIB and SHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth. (wikipedia.org)
Epithelial2
CIP2A cooperates with H-Ras to promote epithelial-mesenchymal transition in cervical-cancer progression. (univ-paris5.fr)
PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. (univ-paris5.fr)
Proliferation1
H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts. (univ-paris5.fr)
LZTR12
LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. (univ-paris5.fr)
LZTR1 is a regulator of RAS ubiquitination and signaling. (univ-paris5.fr)
Cancers1
In humans, other members of the Ras subfamilies carry mutations in human cancers. (wikipedia.org)
Promoter2
In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1 . (nature.com)
Among PTMCs, the prevalence of mutations in rat sarcoma (RAS) and telomerase reverse transcriptase (TERT) promoter was not significantly different according to their size, but lower than in large PTCs. (bvsalud.org)
Protein3
Its N-terminal amino acid sequence shares 60-75% identity with that in the Ras protein while its effector region is identical with that in Ras. (wikipedia.org)
Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). (biomedcentral.com)
Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. (biomedcentral.com)
Inactive1
Son of sevenless (SOS) is then recruited to the plasma membrane and catalyzes the conversion of inactive Ras-GDP to active Ras-GTP that in turn recruits Raf to the plasma membrane. (springer.com)
Cellular1
Autophagic activity dictates the cellular response to oncogenic RAS. (univ-paris5.fr)
Validation of R-Ras and R-Ras2 action and R-Ras regulated networks was performed using genetic and/or pharmacologic approaches. (biomedcentral.com)
Survival1
M-Ras has been found to induce Akt kinase activity in the PI3-K pathway, and it may play a role in cell survival of neural-derived cells. (wikipedia.org)
Molecular1
Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. (niepokorny.org)
Cell1
Interplay between oncogenic K-Ras and wild-type H-Ras in Caco2 cell transformation. (univ-paris5.fr)
Found1
Of the two states M-Ras can switch between, M-Ras is predominantly found in its state 1 conformation, which does not bind Ras effectors. (wikipedia.org)
Activation1
M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes. (wikipedia.org)
Cells3
More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton. (wikipedia.org)
R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. (biomedcentral.com)
Both R-Ras and R-Ras2 are expressed in MPNST cells and activated. (biomedcentral.com)
Family2
More currently, Ras family members such as R-RAS, R-RAS2 and also R-RAS3 have also been implicated as main factors in triggering neural transformation, with R-RAS2 as the most significant element. (wikipedia.org)
First linked to human cancer in 1982 (1C3), members of the RAS family of GTPases (which comprises is the area in the yellow box enlarged, showing hydrogen bonds as thin dashed lines and cationC interaction as a thick dashed line. (niepokorny.org)