CYFIP1

Official Full Name

cytoplasmic FMR1 interacting protein 1

Organism

Homo sapiens

GeneID

23191

Background

This gene encodes a protein that regulates cytoskeletal dynamics and protein translation. The encoded protein is a component of the WAVE regulatory complex (WRC), which promotes actin polymerization. This protein also interacts with the synaptic functional regulator FMR1 protein and translation initiation factor 4E to inhibit protein translation. A large chromosomal deletion including this gene is associated with increased risk of schizophrenia and epilepsy in human patients. Reduced expression of this gene has been observed in various human cancers and the encoded protein may inhibit tumor invasion. [provided by RefSeq, Mar 2022]

Synonyms

SHYC; SRA1; SRA-1; P140SRA-1;

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Detailed Information

Recent Research Progress

Cyfip1 [cytoplasmic FMRP-interacting protein 1 or specific Rac1-related protein 1 (SRA1)] is known to interact with FMRP (fragile X syndrome mental retardation protein), a mutation in fragile X syndrome (FXS) Protein, which has the function of inhibiting protein translation. Cfyip1 also contributes to the formation of the WAVE regulatory complex (WRC), which regulates actin polymerization in synapses. Recently, it has been shown that the functions of these two different protein complexes involving Cyfip1 converge to regulate spinal morphology and synaptic plasticity. These molecular studies have shown that the lack of Cfyip1 may lead to sudden triggering and dysfunction. Human genetic studies have identified Cfyip1 as a gene that is dysregulated in a variety of developmental brain diseases, including specific forms of Angelman and Prader-Willi syndrome, autism spectrum disorders, and schizophrenia.

Cyfip1 and autism and schizophrenia

Recently, studies have found that copy number variation in Cfyip1 is associated with autism, schizophrenia, and intellectual disability (Figure 1). Cfyip1 and the paralog CYFIP2 are enriched at the inhibitory postsynaptic site. Although up-regulation of Cfyip1 or CYFIP2 increases the frequency of excitatory synapses and miniature excitatory postsynaptic currents (mEPSCs), it has an opposite effect in inhibitory synapses, reducing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). In contrast to the up-regulation of Cfyip1, it increases the expression of postsynaptic GABAA receptor b2/3-subunit and neuroligin 3 and enhances synaptic inhibition Cfyip1 after conditional knockout in major cortical major cells. Thus, Cfyip1 doses can affect both inhibitory synaptic structures and functions in both directions, and may result in excitatory/inhibitory (E/I) balance and changes in circuit dysfunction in Cfyip1-related neurological disorders.

Figure 1. Copy number variation (CNV) in CYFIP1 is associated with neuropsychiatric disorders. (Elizabeth C, et al. Cell Reports, 2019)

Cyfip1 and ALL

The mRNA and protein expression levels of Cyfip1 in ALL patients were significantly lower than those in normal peripheral blood lymphocytes (PBL). In addition, both mRNA and protein expression were negatively correlated with lymph node metastasis. In conclusion, detection of Cyfip1 mRNA and protein expression can provide clinically important information related to diagnosis, progression, and treatment modalities for ALL, and Cyfip1 may serve as a potential biomarker for diagnosis and prognosis in ALL.

Cyfip1 and SCC

Squamous cell carcinoma of the skin (SCC) represents one of the most common cancers in the general population and has a significant risk of metastasis. Cyfip1 expression has been reported to be down-regulated in SCC and inversely proportional to the histological differentiation of tumors. Cyfip1 mRNA is highly increased in human Notch1 overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes affected Cyfip1 levels, and chromatin immunoprecipitation assay confirmed that Notch1 binds directly to the Cyfip1 promoter. Cyfip1 may be a link between differentiation loss and invasive ability in malignant keratinocytes of cutaneous squamous cell carcinoma.

The results indicate that Cyfip1 is usually absent in epithelial colon, breast or lung cancer. A decrease in the expression of Cyfip1 was also observed during the invasion of these tumors and was associated with poor prognosis. Since Cyfip1 is commonly found in many diseases, its dysregulation seems to exacerbate symptoms, so the treatment of Cyfip1 function may be beneficial for many human diseases.

References:

Leeyup Chung, et al. Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficiency mice. Brain Res. 2015, 10(1629):340–350.
Kuangfu Hsiao, et al. Cyfip1 Regulates Presynaptic Activity during Development. The Journal of Neuroscience, 2016, 36(5):1564–1576.
Elizabeth C, et al. Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition. Cell Reports, 2019, 26:2037–2051.
Wang Jian, et al. Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism. Annals of Human Genetics, 2015, 79:329–340.
Rebecca A, et al. Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks. Plos One, 2016, 11(1):e0148039.
Piotr J, et al. CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma. Plos One, 2017, 12(4):e0173000.
Chang Jer-Wei, et al. Wild-type p53 up-regulates an early onset breast cancer-associated gene GAS7 to suppress metastasis via GAS7–CYFIP1-mediated signaling pathway. Oncogene, 2018, 37:4137–4150.

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