CSF3R

Fig1. Transcription Factors of GCSFR (CSF3R). (Sungjin David Park, 2022)

What is CSF3R protein?

CSF3R gene (colony stimulating factor 3 receptor) is a protein coding gene which situated on the short arm of chromosome 1 at locus 1p34. The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. The CSF3R protein is consisted of 836 amino acids and CSF3R molecular weight is approximately92.2 kDa.

What is the function of CSF3R protein?

CSF3R protein is a receptor for granulocyte colony-stimulating factor and is essential for the production, differentiation and function of neutrophils. By binding to G-CSF, it activates the downstream JAK/STAT signaling pathway and promotes cell proliferation and survival. Mutations in CSF3R can lead to a number of blood disorders, such as severe congenital neutropenia. In addition, CSF3R expression levels are abnormal in some cancers, making it a potential therapeutic target, especially in the treatment of acute myeloid leukemia. Studying the function and regulatory mechanisms of CSF3R is critical to understanding its role in disease.

CSF3R related signaling pathway

The CSF3R signaling pathway is crucial for the regulation of myeloid cell proliferation, differentiation, and survival. Upon binding of its ligand, CSF3 (also known as Granulocyte Colony-Stimulating Factor, G-CSF), CSF3R undergoes dimerization and autophosphorylation, initiating a series of intracellular signaling cascades primarily involving the JAK-STAT pathway. This activation promotes the transcription of genes essential for neutrophil production and function, thereby enhancing immune response against infections. Dysregulation of this pathway can lead to hematological disorders such as leukemia, underscoring its importance in maintaining normal hematopoiesis.

CSF3R related diseases

The CSF3R protein is a receptor for granulocyte colony-stimulating factor (G-CSF) and plays a key role in regulating the development, function and survival of neutrophils. Mutations in the CSF3R gene are associated with a variety of blood disorders, including chronic neutrophil leukemia (CNL), severe congenital neutropenia (SCN), acute myeloid leukemia (AML), and other myeloid tumors. In addition, abnormal expression of CSF3R is also involved in the development of some solid tumors. CSF3R activation mutations can lead to sustained activation of signaling pathways, thereby promoting cell proliferation and survival and contributing to tumor occurrence and progression.

Bioapplications of CSF3R

In clinical applications, CSF3R is involved in regulating the hematopoietic process by binding with its ligand G-CSF, which is clinically used to shorten the recovery time of chemotherapy and promote hematopoietic stem cells to enter the peripheral blood for stem cell collection. In addition, mutations in CSF3R are associated with a variety of blood disorders, and CSF3R has emerged as a potential target for the treatment of blood disorders, for example, JAK inhibitors that target CSF3R mutations have shown clinical efficacy in the treatment of certain leukemia patients. In addition, the expression level of CSF3R can also be used as a biomarker for hematological malignancies, helping to monitor disease progression and treatment response.

Case Study 1: S Rohrabaugh, 2017

Recent findings indicate that CSF3R mutations, both near the membrane and those that result in a truncated protein, can lead to chronic neutrophilic leukemia (CNL). This study found that while a truncated mutation alone isn't sufficient to cause leukemia, the combination of membrane-proximal and truncated mutations on the same allele can, with different disease onsets. The increased expression of the Mapk adaptor protein Ksr1 and heightened Mapk signaling are key to the development of leukemia from these CSF3R mutations. Importantly, MEK1/2 inhibition with trametinib can effectively treat leukemia caused by both types of CSF3R mutations, including those resistant to ruxolitinib. These results highlight the role of Mapk signaling in CSF3R-induced leukemia and support the exploration of MEK1/2 inhibitors as a treatment for CNL.

Fig1. Survival curve of mice showing CSF3R proximal and compound mutations induce lethal leukemia.

Fig2. Immunoblots from the total cell extracts of BaF3 cells expressing CSF3R variants probed with anti-HA to determine the expression CSF3R.

Case Study 2: Jing Ai, 2008

The granulocyte colony-stimulating factor receptor (G-CSFR) is essential for the production of granulocytes. Mutations in G-CSFR can lead to severe congenital neutropenia (SCN) and acute myeloid leukemia (AML), causing increased sensitivity to G-CSF. Our study explored the role of ubiquitination in G-CSFR signaling by creating a G-CSFR mutant (K762R/G-CSFR) that cannot attach ubiquitin at a key site. This mutation hindered the normal regulation of G-CSFR signaling, resulting in increased cell proliferation, hypersensitivity to G-CSF, and extended survival. Additionally, the activation of Stat5 and Akt signaling molecules was heightened and sustained in these cells after G-CSF stimulation.

Fig3. Impaired mono-/polyubiquitination of the K762R/G-CSFR in response to ligand binding.

Fig4. Enhanced proliferation and viability of 32D cells expressing the K762R/G-CSFR mutant.

CSF3R has several biochemical functions, for example, cytokine receptor activity,protein binding,receptor activity. Some of the functions are cooperated with other proteins, some of the functions could acted by CSF3R itself. We selected most functions CSF3R had, and list some proteins which have the same functions with CSF3R. You can find most of the proteins on our site.

CSF3R 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 CSF3R here. Most of them are supplied by our site. Hope this information will be useful for your research of CSF3R.

UBC;STAT3