CSF1R

Official Full Name

colony stimulating factor 1 receptor

Organism

Homo sapiens

GeneID

1436

Background

The protein encoded by this gene is the receptor for colony stimulating factor 1, a cytokine which controls the production, differentiation, and function of macrophages. This receptor mediates most if not all of the biological effects of this cytokine. Ligand binding activates the receptor kinase through a process of oligomerization and transphosphorylation. The encoded protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. Mutations in this gene have been associated with a predisposition to myeloid malignancy. The first intron of this gene contains a transcriptionally inactive ribosomal protein L7 processed pseudogene oriented in the opposite direction. Alternative splicing results in multiple transcript variants. Expression of a splice variant from an LTR promoter has been found in Hodgkin lymphoma (HL), HL cell lines and anaplastic large cell lymphoma. [provided by RefSeq, Mar 2017]

Synonyms

FMS; CSFR; FIM2; GPSC; HDLS; C-FMS; CD115; HDLS1; CSF-1R; BANDDOS; M-CSF-R;

Bio Chemical Class

Kinase

Protein Sequence

MGPGVLLLLLVATAWHGQGIPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNTGTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLTDPVLEAGVSLVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASSVDVNFDVFLQHNNTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAYLNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTYRHTFTLSLPRLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTDRCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFIPISAGAHTHPPDEFLFTPVVVACMSIMALLLLLLLLLLYKYKQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLGAGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHENIVNLLGACTHGGPVLVITEYCCYGDLLNFLRRKAEAMLGPSLSPGQDPEGGVDYKNIHLEKKYVRRDSGFSSQGVDTYVEMRPVSTSSNDSFSEQDLDKEDGRPLELRDLLHFSSQVAQGMAFLASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDIMNDSNYIVKGNARLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGILVNSKFYKLVKDGYQMAQPAFAPKNIYSIMQACWALEPTHRPTFQQICSFLQEQAQEDRRERDYTNLPSSSRSGGSGSSSSELEEESSSEHLTCCEQGDIAQPLLQPNNYQFC

Open

Disease

Alzheimer disease, Bone/articular cartilage neoplasm, Diabetes mellitus, Idiopathic interstitial pneumonitis, Inflammatory arthropathy, Malignant haematopoietic neoplasm, Motor neuron disease, Pancreatic cancer, Phakomatoses/hamartoneoplastic syndrome, Solid tumour/cancer, Stomach cancer

Approved Drug

1 +

Clinical Trial Drug

14 +

Discontinued Drug

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Detailed Information

The CSF1R gene (Colony Stimulating Factor 1 Receptor gene) encodes a receptor tyrosine kinase that plays an important biological function on the cell membrane. Moreover, mutations in the CSF1R gene are closely associated with the occurrence of various diseases, especially those related to the immune and nervous systems, such as hereditary diffuse leukoencephalopathy with spheroids (HDLS) and osteopetrosis. Mutations in the CSF1R gene can lead to significant white matter damage and neurodegeneration, suggesting the importance of CSF1R in the development and maintenance of microglia in the brain.

Figure 1 illustrates the proposed CSF1R-mediated signaling, where ligands CSF1 or IL34 stimulate CSF1R dimerization and activation of pathways like PI3K/Akt, regulating microglial proliferation and survival, with interaction via TREM2/DAP12. Figure 1. Proposed CSF1R-mediated signaling pathway in microglial proliferation and survival. (Hu B, et al., 2021)

CSF1R Signaling Pathway and Immune Response

Apart from the formation of immune cells, CSF1R is crucial in several immunological-related disorders as well. Tumour immune escape and progression in the tumors microenvironment (TME) is much influenced by the interaction of CSF1R with tumors associated macrophages (TAMs). Through their upregulation of CSF1, tumor cells attract macrophages to assemble at their location. In the tumor microenvironment, these macrophages often show pro-tumor actions including immunosuppression, angiogenesis promotion, and release of many pro-tumor cytokines (like TGF-β, IL-10, etc.). Tumors may evade the immune monitoring of the host through this immunosuppressive impact, therefore fostering tumor development and metastases.

A major tactic in tumor immunotherapy is now the inhibition of CSF1R. Reducing the binding of CSF1 with CSF1R helps to lower the concentration of TAMs, particularly those with M2-type properties, therefore enhancing the anti-tumor immune response. CSF1R inhibitors have shown promise in preclinical and clinical research in stopping the development of many types of tumors. In treating glioblastoma (GBM), for instance, CSF1R inhibitors may help to lower M2-type TAM concentration, change the tumor microenvironment, and improve tumor sensitivity to immunotherapy.

CSF1R Mutations and Hereditary Diseases

Different hereditary disorders are strongly linked to mutations in CSF1R; the most common one is CSF1R-related diffuse leukoencephalopathy with spheroids (HDLS). Often coupled with early cognitive and motor dysfunctions, HDLS is a neurodegenerative illness. Usually beginning at 40 to 50 years of age, patients have symptoms akin to behavioral variant frontotemporal dementia (bvFTD), then show motor symptoms including tremor, rigidity, and bradykinesia. Particularly weakening of the corpus callosum and limited diffusion lesions in the white matter, brain imaging examinations reveal significant anomalies in the white matter. From pathologically, HDLS shows as axonal injury and myelin loss.

In this condition, microglia malfunction results from CSF1R gene alterations. Microglia are the primary immune cells in the brain; they help with immune surveillance and brain repair. White matter degeneration results from these cells failing to form or function as caused by CSF1R mutations. In such disorders, CSF1R gene alterations not only influence microglia's functioning but also can cause their buildup in the brain and initiate neurotoxic effects.

CSF1R and Tumor Immunotherapy

The possible use of CSF1R in tumor immunotherapy has been investigated in great detail lately. High expression of CSF1 and its receptor CSF1R has been noted in numerous malignancies, including forms of cancers like breast cancer, ovarian cancer, and kidney cancer. Tumor-associated macrophages, which enable the tumor to evade immune monitoring via immunosuppressive processes, are intimately linked with CSF1R. Consequently, aiming at CSF1R is seen as a sensible approach for treating tumors.

Clinical studies for CSF1R inhibitors' effectiveness in different cancer therapies are in progress right now. Research indicates that by "re-educating" these cells, CSF1R inhibitors may efficiently reduce TAM growth and transform them into M1-type macrophages with anti-tumor action. Various tumor models, including glioblastoma and colorectal cancer, have demonstrated some effectiveness for such treatments. To get better therapeutic results in certain malignancies, CSF1R inhibitors may potentially be used in conjunction with other immunotherapy approaches such as immune checkpoint inhibitors.

References:

Wen J, Wang S, et al. CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment. Eur J Med Chem. 2023 Jan 5;245(Pt 1):114884.
Konno T, Kasanuki K, et al. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. Neurology. 2018 Dec 11;91(24):1092-1104.
Hu B, Duan S, Wang Z, et al. Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders. Front Aging Neurosci. 2021;13:789834.
Cannarile MA, Weisser M, et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017 Jul 18;5(1):53.

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