The receptors for platelet-derived growth factor (PDGF) and stem cell factor

The receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF) are members of the type III class of PTK receptors which are characterized by five Ig-like domains extracellularly and a split kinase domain name intracellularly. BIBX 1382 fusions point mutations and amplifications-drive subpopulations of certain malignancies such as gastrointestinal stromal tumors chronic myelomonocytic leukemia hypereosinophilic syndrome glioblastoma acute myeloid leukemia mastocytosis and melanoma. The type III tyrosine kinase receptor family consists of platelet-derived growth factor (PDGF) receptor α and β stem cell factor (SCF) receptor (Kit) colony-stimulating factor-1 (CSF-1) receptor and Flt-3 (Blume-Jensen and Hunter 2001). Members of this receptor family are seen as a five Ig-like domains within their extracellular component an individual transmembrane site and an intracellular component consisting of a fairly well-conserved juxtamembrane site a tyrosine kinase site with a quality inserted series without homology with kinases along with a much less well-conserved carboxy-terminal tail. The ligands for these receptors are dimeric substances and on binding they induce receptor dimerization. Even though overall F2R systems for the activation of the sort III tyrosine kinase receptors as well as the signaling pathways they induce are identical the receptors are indicated on different cell types and therefore have different features in vivo. Right here we will describe the structural and functional properties from the PDGF Package and receptors. PDGF RECEPTORS Ligand-Binding Specificities of PDGF Receptors The PDGF family members includes five people (i.e. disulfide-bonded dimers of homologous A- B- C- and D-polypeptide stores as well as the Abdominal heterodimer) (Heldin and Westermark 1999). The PDGF-α receptor binds all PDGF stores except the D string whereas the β receptor binds PDGF-B and -D; therefore the various PDGF isoforms can induce αα- αβ- or ββ-receptor dimers (Fig. 1). The ligand-binding sites can BIBX 1382 be found in Ig-like domains 2 and 3 (Heidaran et al. 1990; Lokker et al. 1997; Miyazawa et al. 1998; Shim et al. 2010); nevertheless ligand-induced receptor dimerization can be stabilized by immediate receptor-receptor relationships in Ig-like domains 4 and 5 (Omura et al. 1997; Yang et al. 2008). The second option relationships are important simply because they BIBX 1382 orient the receptors in order that their activation by autophosphorylation in can be facilitated. Binding of vascular endothelial development element (VEGF)-A to PDGFR-α and PDGFR-β continues to be reported (Ball et al. 2007) however the physiological need for this finding continues to be to become elucidated. Shape 1. Ligand-binding specificities of SCF and PDGF receptors. The BIBX 1382 various ligands are depicted above the particular receptor dimers they bind to. Binding of PDGF-CC and PDGF-DD to αβ-heterodimeric PDGF receptors have already been referred to but additionally … Ligand excitement leads to homo- in addition to heterodimerization of -β and PDGF-α receptors; the various dimeric receptor complexes possess overlapping but somewhat different signaling capacities (discover further below). Nevertheless PDGF receptors may also type complexes with additional tyrosine kinase BIBX 1382 receptors like the epidermal development element (EGF) receptor (Saito et al. 2001) and fibroblast development element (FGF) receptor-1 (Faraone et al. 2006) but additionally with nonkinase receptors such as for example integrins (Sundberg and Rubin 1996; Schneller et al. 1997) Compact disc44 (Li et al. 2006) the low-density lipoprotein receptor-related proteins (LRP) (Boucher et al. 2002; Loukinova et al. 2002) as well as the poliovirus receptor Necl-5 (Minami et al. 2010). Such relationships modulate signaling via PDGF receptors. Activation of PDGF Receptor Kinases PDGF-induced receptor dimerization results in autophosphorylation of particular tyrosine residues within the intracellular elements of the receptors. Therefore the α and β receptors possess 10 and 11 autophosphorylation sites respectively (Fig. 2) (Heldin et al. 1998). The autophosphorylation acts two important features: It results in adjustments in the conformation from the intracellular elements of the receptors advertising their activation and it offers docking sites for SH2-domain-containing sign transduction substances. Figure 2. Binding of SH2-containing signaling substances to phosphorylation sites in SCF and PDGF receptors. The known phosphorylated tyrosine residues as well as the substances that bind for them.