CSF1R（巨噬細胞集落刺激因子受體）是CSF1信號轉導的關鍵分子，它能夠通過下游信號通路影響細胞的增殖、分化、遷移和存活等過程。CSF1R在免疫細胞的發育、巨噬細胞的極化和炎癥反應的調節等方面發揮著重要作用。最近的研究表明，CSF1R在多種疾病中的異常表達和活化與其發生和發展密切相關，例如肥胖癥、自身免疫性疾病和腫瘤等。

Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathway. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. In the central nervous system, may play a role in the development of microglia macrophages.

1. M-CSFR inhibition suppressed programmed death-1 and -2 ligand in adult T-cell leukemia/lymphoma (ATLL) cells and macrophages stimulated with conditioned medium from ATL-T cells. PMID: 30541986
2. The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP. PMID: 30136118
3. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 axonal spheroids and pigmented glia cases who had CSF1R mutations PMID: 28921817
4. Study find elevated expression of CSF1R in primary gastric cancer tissue (GC) to be significantly associated with the presence of lymph node and peritoneal metastasis, advanced TNM stage, and poor survival. In vitro analysis also revealed a functional role for the CSF1R in GC development, and a prognostic and predictive biomarker for GC. PMID: 29767252
5. Adult-onset Mendelian leukodystrophy genes are not common factors implicated in Alzheimer's disease, but there is a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset Alzheimer's disease. PMID: 29544907
6. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.(S39-S41) is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. PMID: 28827005
7. this is the first study to demonstrate CSF1R genetic variant regulates the CSF-1R signaling and sensitivity to CSF-1R inhibitors. PMID: 28724665
8. Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR. PMID: 27602954
9. CSF-1R is a novel therapeutic target. PMID: 27334834
10. The phenotype of adult-onset leukoencephalopathy axonal spheroids and pigmented glia caused by CSF1R mutations is affected by sex PMID: 27680516
11. CSFIR mutation is associated with Metaplastic Breast Cancer. PMID: 27568101
12. Results suggest that TP63 rs7631358 G > A and CSF1R rs10079250 A > G may affect the risk and prognosis of lung cancer in never-smoking females. PMID: 28449811
13. findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids. PMID: 27190017
14. This review showed that CSF1R mutation is related to Hereditary diffuse leukoencephalopathy with axonal spheroids. PMID: 27338940
15. High CSF-1R expression is associated with Clear Cell Renal Cell Carcinoma. PMID: 26467457
16. The aim of this study was to compare the expression of CSF-1R in nasopharyngeal carcinoma to nasopharyngitis. PMID: 26743272
17. CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies. PMID: 25935893
18. The frequencies of the rare alleles of CCR2, ITGB3, and 3'UTR of c-fms in the Old Believers are lower than in the sample of Novosibirsk Russians, and the rare allele of DBH is more frequent PMID: 27239844
19. Assessing serum levels of WFA(+) -CSF1R has diagnostic value for predicting carcinogenesis and the survival of LC patients. PMID: 26437001
20. CSF1R pathway activation was evident in the cHL and inactivation of this pathway could be a potential therapeutic target in cHL cases. PMID: 26066800
21. All 4 hereditary diffuse leukoencephalopathy with axonal spheroids patients had a different single nucleotide mutation in the cytoplasmic part of the gene. Different mutations lead to different levels of depletion of nonclassical slan-positive monocytes. PMID: 26443621
22. results suggest that CSF1R SNP rs10079250 may contribute to lung cancer susceptibility in never-smoking females PMID: 25144241
23. Report treatment of diffuse-type tenosynovial giant cell tumour of the soft tissue using CSF1R inhibition with emactuzumab. PMID: 26179200
24. Autocrine CSF1R signaling is essential in maintaining low claudin expression. PMID: 25088194
25. CSF1R gene had variations in genic regions that affected the association of RORalpha with its target binding site in vivo PMID: 25913741
26. The first report of hereditary diffuse leukoencephalopathy with neuroaxonal spheroids due to a novel CSF1R missense mutation. PMID: 25012610
27. A missense mutation c.2563C>A (p.P855T) of the CSF1R gene has been identified to associated with hereditary diffuse leukoencephalopathy. PMID: 25863088
28. CSF-1R D802V and KIT D816V homologous mutations have differential effects on receptor tertiary structure and allosteric communication. PMID: 24828813
29. C/EBPalpha-C(m)-mediated downregulation of Csf1r has a negative, rather than positive, impact on the progression of AML involving C/EBPalpha-C(m), which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation PMID: 25534203
30. The survival of CSF1R(pos) cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent beta-catenin. PMID: 24722292
31. CSF1R gene analysis was performed in 15 patients with undefined leukoencephalopathy and progressive cognitive decline PMID: 24532199
32. We report three patients with HDLS who carried missense mutations in the CSF1R gene, two of them novel (p.L582P and p.V383L). PMID: 24706185
33. The identified isoform of CSF-1R mRNA may interfere with the expression of full-length CSF-1R mRNA, thereby affecting the biological activity of the ligand/receptor signaling axis in Sprague-Dawley rats. PMID: 24682770
34. CSF-1R mayact as a transcriptional regulator on proliferation-related genes in breast cancer. PMID: 24362524
35. Our results provide new insights into the molecular physiology of the CSF-1 receptor and contribute to our understanding of substrate selection by TACE and gamma-secretase. PMID: 24955855
36. haploinsufficiency of CSF-1R is sufficient to cause Hereditary diffuse leukoencephalopathy with spheroids [review] PMID: 24807373
37. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. PMID: 24145216
38. diagnosis of HDLS or a de novo mutation in CSF1R must be considered in patients with bilateral symmetric changes in ukodystrophies. PMID: 24034409
39. Data indicate that anti-CD115 monoclonal antibody H27K15 exerts partial inhibitory effects on CD115 signaling, but inhibits monocyte chemotactic protein-1 secretion and reduces interleukin-6 production. PMID: 23924795
40. Our data demonstrate that a high number of non-Hodgkin/Reed-Sternberg cells expressing CSF-1R are correlated with an increased tumor macrophage content and worse survival in classical Hodgkin lymphoma. PMID: 24619759
41. Our report emphasizes the presence of atypical Parkinsonism in Hereditary diffuse leukoencephalopathy with spheroids due to CSF1R mutations PMID: 23787135
42. our study indicates that pathogenic mutations in CSF1R are an unlikely cause of multipel sclerosis in the Canadian population PMID: 23889897
43. This study showed that a novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids. PMID: 23816250
44. CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of hereditary diffuse leukoencephalopathy with spheroids PMID: 24336230
45. These results indicate that all of the Fms mutations tested severely impair the kinase activity and most of the mutations also impair the trafficking to the cell surface, further suggesting that hereditary diffuse leukoencephalopathy with spheroids is caused by the loss of Fms function. PMID: 24120500
46. One mechanism of RANK inhibition by 1,25(OH)2D3 is down-regulation of the M-CSF receptor c-Fms, which is required for the expression of RANK. PMID: 23116709
47. Data suggest that CSF-1R-independent actions of IL-34 via receptor-type protein-tyrosine phosphatase zeta (PTP-zeta) might be considered in evaluating IL-34 roles in development and disease. PMID: 23744080
48. CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven hereditary diffuse leukoencephalopathies with spheroids. PMID: 23649896
49. This study showed that Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia with CSF1R mutation. PMID: 23052599
50. CSF1/CSF1R signaling is important in the recruitment of tumor-infiltrating myeloid cells that can limit the efficacy of radiotherapy PMID: 23418320

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Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS)

Cell membrane; Single-pass type I membrane protein.

Protein kinase superfamily, Tyr protein kinase family, CSF-1/PDGF receptor subfamily

Expressed in bone marrow and in differentiated blood mononuclear cells.

HGNC: 2433

OMIM: 164770

KEGG: hsa:1436

STRING: 9606.ENSP00000286301

UniGene: Hs.586219