FRS3

What is FRS3 protein?

FRS3, or Fibroblast growth factor receptor substrate 3, is a protein that in humans is encoded by the FRS3 gene. It interacts with fibroblast growth factor receptors and is involved in signal transduction pathways that regulate cell growth, wound healing, and embryonic development.

Located on chromosome 6 in humans, the FRS3 gene is made up of 553 amino acids. It's a protein that has several important domains and motifs that help it fulfill its functions, such as its phosphotyrosine binding (PTB) domain and its C-terminal region.

The discovery of FRS3 goes hand in hand with the exploration of the fibroblast growth factor receptor (FGFR) system, which is a family of four closely related receptor tyrosine kinases that are highly conserved across vertebrates.

What is the function of FRS3 protein?

FGFRs serve crucial roles in multiple biological functions, including angiogenesis, wound healing, embryonic development, and differentiation. Their ability to regulate these events comes from their interactions with adaptor proteins such as the FRS2 and FRS3 proteins.

The cellular functions of FRS3 are still being explored, but early research suggests that its roles may include aiding in the negative regulation of receptor activation, or helping to mediate cell signals that control cell growth and survival.

FRS3 related signaling pathway

FGF/FGFR/Ras/MAPK pathway: Upon FGFR activation, FRS3 becomes phosphorylated and recruits Grb2, activating Ras and the downstream MAPK/Erk cascade. This mediates FGFR-driven proliferation and cell cycle progression.

FGF/FGFR/PI3K/Akt pathway: Phosphorylated FRS3 recruits PI3K to activated FGFRs, initiating the PI3K/Akt survival pathway. This regulates processes like apoptosis inhibition.

PLCγ pathway: FRS3 binds and activates PLCγ upon FGFR stimulation. PLCγ then generates IP3 and DAG, triggering PKC and calcium mobilization. This influences cell migration, adhesion and differentiation.

FRS3 Related Diseases

Cancers: FRS3 overexpression contributes to proliferation, angiogenesis and survival of certain tumor types like glioma, lung cancer and melanomas.

Neurological disorders: Altered FRS3 levels impact FGFR-dependent processes in brain development, implicated in conditions like schizophrenia and autism.

Lung diseases: Variants that reduce FRS3 activation predispose to COPD by dampening tissue repair mechanisms.

Metabolic disorders: Frs3 knockout mice show increased insulin sensitivity, pointing to roles in diabetes and obesity.

Biomedical Application of FRS3 Protein

Cancer therapy: Targeting overexpressed FRS3 is a strategy to inhibit FGFR-driven tumor growth and angiogenesis.

Drug development: Screening for small molecule FRS3 inhibitors/modulators to control FGFR signaling hyperactivation in diseases.

Biomarker: Aberrant tissue/blood FRS3 levels can indicate activation states of FGFR pathways in cancers and other disorders.

Case 1: Hanes R,et al. Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells. 2019 Feb 21;8(2):189. doi: 10.3390/cells8020189. PMID: 30795553; PMCID: PMC6406403.
FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but the researchers previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398.Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis in vitro and also testing efficacy in vivo. Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway.
Their study supports LY2874455 as a better therapy than NVP-BGJ398 for FRS2-amplified liposarcoma, and a clinical trial is warranted.

Fig1. Signaling pathway analysis after FGFR stimulation and inhibition in NRH-LS1, LPS510 and LPS853. Western blots showing (A) The level of phosphorylated and total protein for the indicated proteins in NRH-LS1 cells treated for 24 h with 100 nM of LY2874455 or 100 nM NVP-BGJ398, with or without FGF stimulation as indicated; (B) The level of phosphorylated and total protein for the indicated proteins in NRH-LS1, LPS510 and LPS853 cells treated for 24 h with 100 nM of LY2874455, with or without FGF as indicated. In all Western blot experiments α-tubulin was used as a loading control.

Case 2: Jing W, et al. Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data. Diagn Pathol. 2021 Oct 25;16(1):96. doi: 10.1186/s13000-021-01161-9. PMID: 34696768; PMCID: PMC8543942.
The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4 within the 12q13-15 chromosomal region. FRS2 gene was recently found to be consistently amplified in atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL), suggesting the detection of FRS2 amplification could be a diagnostic tool for ALT/WDL/DDLs.
FRS2 fluorescence in situ hybridization (FISH) and IHC were performed on 182 ALT/WDL/DDLs and 64 control samples. The expression of FRS2 was also compared with that of classic immunomarkers (MDM2 and CDK4) of this tumor entity.
This study indicated that FRS2 IHC had relatively good consistency with FRS2 FISH, suggesting that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT/WDL/DDL.

Fig1. The histologic features of ALT/WDLs and corresponding FRS2 FISH and FRS2 immunostaining results. Lipoma-like ALT/WDL(a) with FRS2 amplification (inset), showing 3+ FRS2 expression with diffuse and strong cytoplasmic staining (b). Sclerotic ALT/WDL(c) showing FRS2 amplification (inset), displayed 3+ FRS2 immunostaining, with strong FRS2 protein expression

FRS3 has several biochemical functions, for example, fibroblast growth factor receptor binding,identical protein binding,insulin receptor binding. Some of the functions are cooperated with other proteins, some of the functions could acted by FRS3 itself. We selected most functions FRS3 had, and list some proteins which have the same functions with FRS3. You can find most of the proteins on our site.

FRS3 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with FRS3 here. Most of them are supplied by our site. Hope this information will be useful for your research of FRS3.

PIK3R3;q9wmx2-pro_0000037548;PLSCR1;SPRY2;TCF4;GATA1;AES