Search results for CSF1R

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Identifier: R-HSA-9842663
Species: Homo sapiens
Leukocyte tyrosine kinase (LTK) is a transmembrane receptor tyrosine kinase that is a member of the insulin growth factor receptor superfamily. LTK is most closely related to the ALK receptor, and may have originated as a result of a duplication event of the ALK gene (Krowelski and Dalla-Favera, 1991; Dornburg et al, 2021). The extracellular domains of ALK and LTK are characterized by a membrane proximal EGF-like (EGFL) module, a unique 250 amino acid glycine rich (GR) domain that, in Drosophila, is essential for function (Englund et al, 2003), as well as a TNF-like (TNFL) module. The ALK ECD additionally contains two MAM domains, an LDLa domain and a heparin-binding domain (HBD) that are not present in the LTK receptor (Iwahara et al, 1997; Morris et al, 1997; DeMunck et al, 2021). These differences in ECD may contribute to differences in the ligand binding affinities of the two receptors.
LTK is activated by the binding of cytokines ALKAL1 and ALKAL2 to the ECD (Zhang et al, 2014; Reshetnyak et al, 2015; Reshetnyak et al, 2018). Ligand binding induces trans-autophosphorylation in the intracellular domain of the receptor and promotes the interaction and activation of downstream signaling molecules such as SHC, IRS1, CBL and PI3K with the phosphorylated receptor (Kozutsumi et al, 1994; Honda et al, 1994; Ueno et al, 1995; Ueno et al, 1996; Ueno et al, 1997; Li et al, 2004; Yamada et al, 2008). Note however that much of the early functional studies on LTK were conducted before the identification of ALKAL1 and 2 as physiological ligands. In consequence, many of these studies were carried out using chimeric receptors consisting of the ECD (and stimulating ligands) of well-characterized receptors fused to the intracellular domain of LTK.
The exact role of LTK signaling is likewise not fully elucidated. Expression of the chimeric LTK proteins described above promotes neurite outgrowth and cell survival (Ueno et al, 1997; Yamada et al, 2008). A role for LTK in the regulation of transport from the ER to the Golgi has also been proposed, and one study suggests that LTK may actually bean ER-resident protein (Farhan et al, 2010; Centonze et al, 2019). More recently, fusions of LTK have been identified in non-small cell lung cancer (Izumi et al, 2021).
Identifier: R-HSA-9680350
Species: Homo sapiens
Colony stimulating factor-1 (CSF1, CSF-1, also called macrophage colony stimulating factor, M-CSF) is a disulfide-linked dimer that stimulates the proliferation and differentiation of mononuclear phagocytes and the survival, proliferation, motility, and anti-inflammatory activity of macrophages (reviewed in Mouchemore et al. 2012, Stanley and Chitu 2014, Ushach and Zlotnik 2016, Dwyer et al. 2017 and inferred from mouse homologs in Caescu et al. 2015). The unliganded CSF1 receptor, CSF1R (CSF-1R) is either clustered or undergoing rapid dimer-monomer transitions at the cell surface (Li and Stanley 1991). The CSF1 dimer initially binds the D2 and D3 extracellular domains of a monomer of CSF1R (Wang et al. 1993, Chihara et al. 2010, Ma et al. 2012, Felix et al. 2015, and inferred from mouse homologs). A second monomer of CSF1R then binds the CSF1:CSF1R complex and the resulting dimerization of CSF1R activates its kinase activity (Elegheert et al. 2011, Felix et al. 2015, and inferred from mouse homologs). CSF1R initially trans-autophosphorylates tyrosine-561 in the juxtamembrane domain, relieving negative autoinhibition of kinase activity, resulting in the trans-autophosphorylation of 7 more tyrosine residues in its cytoplasmic domain (Rohrschneider et al. 1997, Chihara et al. 2010, and inferred from mouse homologs in Xiong et al. 2011).
The PIK3R1 (p85alpha) regulatory subunit of phosphatidylinositol 3-kinase (PI3K) binds phosphotyrosine-723 of CSF1R, phosphorylated SRC binds phosphotyrosine-561 of CSF1R, phosphorylated CBL binds CSF1R associated with SHC, and GRB2:SOS binds CSF1R (Saleem et al. 1995, and inferred from mouse homologs). The resulting activation of the catalytic subunit of PI3K (PIK2CA,B,G) produces phosphatidylinositol 3,4,5-trisphosphate which recruits effectors containing pleckstrin homology domains (PH domains) such as PKB (also called Akt) to the plasma membrane. Pathways activated by PI3K appear to both enhance proliferation, survival, and migration of macrophages (reviewed in Dwyer et al. 2017) and, via induction of miR21, suppress the inflammatory response by targeting mRNAs encoding multiple proinflammatory molecules.
Phospholipase C gamma2 (PLCG2) binds phosphotyrosine-723 of CSF1R, hydrolyzes phosphatidylcholine to yield choline phosphate (phosphocholine) and diacylglycerol, and promotes survival and differentiation of macrophages via PKCdelta (PRKCD) (inferred from mouse homologs).
GRB2 bound to SOS1 (GRB2:SOS1) transiently interacts with phosphotyrosine-699 of CSF1R. SOS1 promotes the exchange of GDP for GTP by KRAS, activating the RAS-RAF-ERK1,2 pathway that causes proliferation of macrophage precursors (inferred from mouse homologs). CBL transiently associates with and ubiquitinates the CSF1R, then is deubiquitinated and returned to the cytoplasm (inferred from mouse homologs).
Phosphorylated CSF1R also recruits STAT1 and STAT3, which are then phosphorylated (inferred from mouse homologs). The role of phosphorylated STAT1,3 in signaling by CSF1R is incompletely characterized.
CSF1R is a target for therapeutics, such as imatinib (reviewed in Kumari et al. 2018).
Identifier: R-HSA-8853884
Species: Homo sapiens
The VENTX (also known as VENT homeobox or VENTX2) gene is a member of the homeobox family of transcription factors. The ortholog of VENTX was first described in Xenopus where it participates in BMP and Nanog signaling pathways and controls dorsoventral mesoderm patterning (Onichtchouk et al. 1996, Scerbo et al. 2012). The zebrafish ortholog of VENTX is also involved in dorsoventral patterning in the early embryo (Imai et al. 2001). Rodents lack the VENTX ortholog (Zhong and Holland 2011). VENTX is expressed in human blood cells (Moretti et al. 2001) and appears to play an important role in hematopoiesis. The role of VENTX in hematopoiesis was first suggested based on its role in mesoderm patterning in Xenopus and zebrafish (Davidson and Zon 2000). VENTX promotes cell cycle arrest and differentiation of hematopoietic stem cells and/or progenitor cells (Wu, Gao, Ke, Giese and Zhu 2011, Wu et al. 2014). Ventx suppression leads to expansion of hematopoietic stem cells and multi-progenitor cells (Gao et, J. Biol.Chem, 2012). VENTX induces transcription of cell cycle inhibitors TP53 (p53) and p16INK4A and activates tumor suppressor pathways regulated by TP53 and p16INK4A (Wu, Gao, Ke, Hager et al. 2011), as well as macrophage colony stimulating factor receptor (CSF1R) (Wu, Gao, Ke, Giese and Zhu 2011) and inhibits transcription of cyclin D1 (CCND1) (Gao et al. 2010) and Interleukin-6 (IL6) (Wu et al. 2014). Chromatin immunoprecipitation showed that EGR3 transcription factor directly binds to the promoter of IL6 and IL8 genes (Baron VT et al, BJC 2015). While VENTX expression may suppress lymphocytic leukemia (Gao et al. 2010), high levels of VENTX have been reported in acute myeloid leukemia cells, with a positive effect on their proliferation (Rawat et al. 2010). Another homeobox transcription factor that regulates differentiation of hematopoietic stemm cells is DLX4 (Bon et al. 2015). Studies on colon cancer showed that VentX regulates tumor associated macrophages and reverts immune suppression in tumor microenvironment (Le et al. 2018). MEK1 is required for Xenopus Ventx2 asymmetric distribution during blastula cell division. Ventx2 inhibition by MEK1 is required for embryonic cell commitment (Scerbo et al, eLife, 2017). VENTX induces TP53-independent apoptosis in cancer cells (Gao H, Oncotarget, 2016). During Xenopus embryonic development, VENTX ortholog regulates transcription of the sox3 gene (Rogers et al. 2007) as well as the early neuronal gene zic3 (Umair et al. 2018).
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