Involvement in Disease
Diseases associated with CSF1R include Leukoencephalopathy, Hereditary Diffuse, With Spheroids and Brain Abnormalities, Neurodegeneration, And Dysosteosclerosis.
Function
1.Tyrosine protein kinases, as cell surface receptors of CSF1 and IL34, play an important role in the regulation of the survival, proliferation and differentiation of hematopoietic precursor cells, especially monocytes, such as macrophages and monocytes. Promote the release of pro-inflammatory chemokines in response to IL34 and CSF1, thus playing an important role in the process of innate immunity and inflammation. It plays an important role in regulating the proliferation and differentiation of osteoclasts and regulating bone resorption, and is necessary for normal bone and tooth development. This is necessary for the normal fertility of men and women, and the normal development of mammary ducts and acinar structures during pregnancy. Promote the reorganization of the actin cytoskeleton, regulate the formation of membrane folds, cell adhesion and cell migration, and promote the invasion of cancer cells. Activate a variety of signaling pathways in response to ligand binding, including ERK1/2 and JNK pathways (PubMed:20504948, PubMed:30982609). 2.Phosphorylate PIK3R1, PLCG2, GRB2, SLA2 and CBL. The activation of PLCG2 leads to the production of cell signaling molecules triglycerides and inositol 1,4,5-triphosphate, and then leads to the activation of protein kinase C family members, especially PRKCD. The phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. The activated CSF1R also mediates the activation of MAPK1/ERK2 and/or MAPK3/ERK1 and the SRC family kinases SRC, FYN and YES1. The activated CSF1R transmits signals through proteins or adaptor proteins (such as GRB2) that directly interact with phosphorylated tyrosine residues in the cell. Promote the activation of STAT family members STAT3, STAT5A and/or STAT5B. Promote SHC1 and INPP5D/SHIP-1 tyrosine phosphorylation. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, which dephosphorylate the receptor and its downstream effectors and down-regulate through the rapid internalization of the activated receptor. In the central nervous system, it may be involved in the development of microglia macrophages (PubMed: 30982608).
Post-translational modifications
Autophosphorylated in response to CSF1 or IL34 binding. Phosphorylation at Tyr-561 is important for normal down-regulation of signaling by ubiquitination, internalization and degradation. Phosphorylation at Tyr-561 and Tyr-809 is important for interaction with SRC family members, including FYN, YES1 and SRC, and for subsequent activation of these protein kinases. Phosphorylation at Tyr-699 and Tyr-923 is important for interaction with GRB2. Phosphorylation at Tyr-723 is important for interaction with PIK3R1. Phosphorylation at Tyr-708 is important for normal receptor degradation. Phosphorylation at Tyr-723 and Tyr-809 is important for interaction with PLCG2. Phosphorylation at Tyr-969 is important for interaction with CBL. Dephosphorylation by PTPN2 negatively regulates downstream signaling and macrophage differentiation. Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation.
