Embryonal fyn-associated substrate
EFS | |||
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Location (UCSC) | n/a | n/a | |||||||
PubMed search | [1] | [2] |
View/Edit Human | View/Edit Mouse |
Embryonal fyn-associated substrate is a protein that in humans is encoded by the EFS gene. It is also known as CASS3.[3]
History and discovery
EFS (Embryonal Fyn-associated Substrate), also known as SIN (Src INteracting or Signal Integrating protein) was originally identified using cDNA library screening of mouse embryonal libraries for proteins containing
In humans, the 561 amino acid EFS protein acts as a scaffolding protein for cell signaling based on interactions with
Gene
The chromosomal location of the EFS gene is 14q11.2 and its genomic coordinates are 14:23356400-23365633 on the reverse strand in GRChB38p2 (Genome Reference Consortium Human Build 38 patch release 2).
In humans, at least three transcript variants are known for EFS: isoform 1, containing 6 exons end encoding the full-length protein with 561 amino acids; isoform 2, containing 5 exons and encoding a shorter protein (468 amino acids in length); and isoform 3, containing 6 exons and encoding the shortest protein (392 amino acids).
Little is known about the
Protein family
EFS is a member of the CAS (
Structure
Domain | Position | Length | Function |
---|---|---|---|
N-terminal | 1 - 4 | 4 aa | This region has no assigned function |
SH3-domain | 5-68 | 64 aa | Binds to proline-rich motif containing proteins, such as |
SH2-binding region | 69 - 350 | 282 aa | Contains YxxP motifs capable of being phosphorylated on tyrosine residues, then binding SH2 domains. |
Serine rich domain | 351 - 488 | 138 aa | Conserved domain structure encompassing 4 α-helices bundle has a docking function. |
C-terminal | 489 - 561 | 73 aa | Conserved domain structure encompassing 4 α-helices bundle has a docking function; homo- or heterodimerization; focal adhesion targeting. |
As the member of CAS protein family, EFS shares common structural characteristics with other members of the family. This includes 4 defined domains (summarized in Table 1):
- An N-terminal SH3 domain that is highly conserved among the 4 CAS family members, and highly conserved throughout evolution (amino acids 5-68 for human EFS). SH3 domains bind to proline-rich motif containing proteins.[4] The amino acid sequences of the SH3 domains are 70% identical among human EFS, BCAR1, and NEDD9, making this the most highly conserved domain for the whole protein family.[7] Notably, the murine and human EFS SH3 domains are 100% identical, while the rest of the amino acid sequences of mouse and human EFS are only 78% identical.[7] Important binding partners for this region include FAK,[14] PTK2B,[15] C3G,[16] PTP-PEST,[17] PTP1B,[18] CIZ,[19] and FRNK.[20]
- Central "substrate domain" containing multiple repeats of tyrosine residues embedded within specific conserved sequences (YxxP) (amino acids 69-350 for human EFS).
- A serine-rich domain encompassing a 4 α-helixbundle (amino acids 351-488 for human EFS). Although primary amino acid sequence shows considerable divergence versus other CAS family members in this region, structural analysis predicts that this bundle has a highly conserved fold and provides a docking site for family members.
- A C-terminal domain (489-561 amino acids in human EFS) is highly conserved between family members at both primary amino acid sequence and predicted fold.Src SH2 domain. This region is considered to possess a homo- or heterodimerization ability.
There are three protein isoforms of human Efs. hEfs1 and hEfs2 were identified by Ishino et al.[7] hEFS1 (561 aa) represents the human counterpart of mouse embryonal Efs (mEfs1) originally identified. hEFS1 and mEfs1 are 80% identical in their amino acid sequences and 100% identical within the SH3 domain. hEFS2 (468 aa) is identical to hEFS1, except for its lack of the SH3 domain. hEFS3 (392 aa) also lacks a functional SH3 domain and has the same C-terminus and short N-terminal amino acid tail as the full-length protein.[24][25] Although little functional analysis of hEFS2 has been performed, speculatively, given lack of an SH3 domain, abundant hEFS2 may inhibit hEFS1 signaling by titrating partner proteins.[7] As of 2015, there has been no functional analysis of hEFS3.
Function
As a member of the CAS protein family, EFS is a multi-domain docking molecule that lacks any known enzymatic activity, but instead mediates signaling by promoting protein–protein interactions through conserved sequence motifs (Figure 1).[7][26][27]
An important role of EFS as a CAS-family member function is transmission of
In normal untransformed cells, EFS acts as a
Disease association
The well-studied CAS proteins BCAR1 and NEDD9 have important roles in cancer and other pathological conditions, which have been addressed in many studies and reviews.[12][27][30][36][37] EFS has attracted less study. However, the conserved functional properties of EFS relevant to cellular adhesion and migration, and RTK signaling, suggest changes in activity of this protein may also be relevant to cancer and other disease states, influencing prognosis and therapeutic response. The changes in EFS expression and post-translational modification in the context of disease discussed below are summarized in Table 2.
Disease | Study finding for EFS |
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Crohn's disease | The study linked EFS gene to Crohn's disease (p-value 0.039) in humans.[38] |
Rheumatic fever susceptibility | Significantly increased expression after stimulation of peripheral blood mononuclear cells from patients with rheumatoid heart disease.[39] |
Prostate cancer | CpG site hypermethylation of EFS was associated with prediction of biochemical, local, and systemic recurrence of prostate cancer.[40] Decreased EFS expression was shown in advanced prostate cancer compared to normal tissue, which correlated with high metastatic potential.[41] |
Uveal melanoma | High frequency of promoter CpG site methylation and association with a higher risk of metastatic progression.[24] |
HER2+ breast cancer
|
EFS may play a role in trastuzumab resistance mechanism.[42] |
Prolactinoma | EFS may be involved in stem cell regulation, tumor cell invasion, tumor recurrence, and drug resistance.[43] |
Gestational choriocarcinoma | Located in a frequently amplified chromosomal region along with >100 other genes.[44] |
Glioblastoma multiforme
|
One of the genes differentially expressed in two sub-groups of glioblastoma multiforme defined by gene expression profile.[45]
|
Chediak-Higashi syndrome | Direct interaction with LYST protein, which is associated with lysosomal trafficking.[25]
|
Human endometrium expression profiling | Down regulated by 17β-estradiol and progesterone in explants of late proliferative phase endometrium.[11]
|
Role in inflammation and T-Cell function
EFS regulates
EFS has mostly a repressive role of EFS on processes associated with the activation of mature T-cells, including IL-2 pro-inflammatory cytokine secretion and IL-2-dependent clonal expansion of T cells.[9][46] Upon T-cell receptor (TCR) stimulation, EFS dephosphorylation and release of the SRC family kinase FYN and phospholipase C-γ normally lead to self-limitation of the immune response. Consistent with this mechanism, EFS overexpression in T cell-derived cell lines decreased IL-2 concentration in supernatants in response to TCR stimulation,[46] while T cells derived from mice lacking EFS gene showed increased IL-2 production.[9] A dual role of EFS in mature T cells function has been proposed because both overexpression and siRNA knockdown of this protein in cell models resulted in decreased transcriptional activation of IL-2 dependent promoters following TCR stimulation.[46]
Altered EFS function has been associated with various human immunopathological conditions. Although an initial genome-wide association studies (GWAS) study of Crohn's disease did not identify EFS,[47] EFS single nucleotide polymorphisms (SNPs) were subsequently linked to Crohn's disease.[38] SNPs linked to EFS are trans-acting, potentially affecting the level of EFS expression but not its coding sequence.[48]
Another study suggested that EFS might contribute to acute
Cancer
At the level of EFS mRNA expression, the local and systemic recurrence of
In another study, methylation of the EFS CpG island was observed in 69% of cases of uveal melanoma (UM) and only UM with EFS methylation gave rise to metastases.[24] RT-PCR expression analysis revealed a significant inverse correlation between EFS mRNA expression with EFS methylation in UM. EFS methylation was tissue-specific with full methylation in peripheral blood cells, but no methylation in other tissues such as fetal muscle, kidney and brain.
The EFS gene is one of more than 100 of the genes located in a centromeric 10.21 Mb "minimal critical region" on Chromosome 14 that are highly expressed in
At the level of the EFS protein, a study of BT474
Clinical significance
Based on the above discussion, it is possible that therapeutic benefits can be achieved by using EFS expression or phosphorylation as a marker of disease progression and prognosis in some forms of cancer. Further assessment of EFS expression, mutational status, and potential polymorphic variants may be of use in understanding the biology and developing treatment strategies for immune system pathologies such as CHS. There are currently no therapeutic approaches targeting EFS, and given the protein lacks a catalytic domain and extracellular moieties, it may be challenging to generate such agents.
Notes
PMID 26119091 . |
References
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