Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex

Tao, Ye; Ip, Jacque Pak Kan; Fu, Amy Kit Yu; Ip, Nancy Y.

doi:10.1038/ncomms5826

Cited by 68 publications

(58 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary RASopathy gene SPRED1 is a negative regulator of the pathway; MAP3K2 encodes MEK kinase 2; RAPGEF2 encodes a Ras activator thought to control developmental neuronal migration in the cortex and formation of the corpus callosum[118,119]. ELK3 encodes a transcription factor downstream of Ras/MAPK signaling; ETS1 and GATA3 are additional transcription factors with demonstrated relationships to Ras/MAPK signaling described above[120,121].…”

Section: Discussionmentioning

confidence: 99%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

View full text Add to dashboard Cite

Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The SNP rs72679931 is located between Rap Guanine Nucleotide Exchange Factor (GEF) 2 ( RAPGEF2 ) and Follistatin-Like 5 ( FSTL5 ). The cdk5-mediated phosphorylation of RAPGEF2 has been demonstrated to control neuronal migration in developing cerebral cortex [30]. Mutation of RAPGEF2 in mice can affect the formation of the cerebral cortex and reduce the threshold for the induction of epileptic seizure; in addition, copy number variants of RAPGEF2 in humans may confer higher risk of familial schizophrenia [31].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans

et al. 2016

View full text Add to dashboard Cite

The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1,979 AAs and 6,582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10−8). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson’s or Alzheimer’s disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.

show abstract

“…CDK5 was originally characterized as a neuronal protein involved in cell migration, adhesion and cytoskeletal remodeling (33). These processes are important in cancer progression, and CDK5 has also been shown to be important for these processes in cancer cells, in a cell-specific manner, through phosphorylation of target proteins including FAK, Talin, RAPGEF2, and PIKE-A (34–39). CDK5 participates in cell growth and survival, in part by phosphorylation of targets including Rb, NOXA and STAT3 (40–45).…”

Section: Discussionmentioning

confidence: 99%

Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Dadon

Chenna

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., t.i.w.) and MK-2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP approved multicenter Phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened.

show abstract

Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex

Cited by 68 publications

References 51 publications

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans

Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Contact Info

Product

Resources

About