Ptor (EGFR), the vascular endothelial growth element receptor (VEGFR), or the platelet-derived development element receptor (PDGFR) loved ones. All receptor tyrosine kinases (RTK) are transmembrane proteins, whose amino-terminal end is extracellular (transmembrane proteins kind I). Their general structure is comprised of an extracellular ligandPhorbol binding domain (ectodomain), a modest hydrophobic transmembrane domain plus a cytoplasmic domain, which consists of a conserved area with tyrosine kinase activity. This area consists of two lobules (N-terminal and C-terminal) that form a hinge where the ATP needed for the catalytic reactions is positioned [10]. Activation of RTK takes place upon ligand binding at the extracellular level. This binding induces oligomerization of receptor monomers, normally dimerization. Within this phenomenon, juxtaposition in the tyrosine-kinase domains of each receptors stabilizes the kinase active state [11]. Upon kinase activation, every monomer phosphorylates tyrosine residues in the cytoplasmic tail with the opposite monomer (trans-phosphorylation). Then, these phosphorylated residues are recognized by cytoplasmic proteins containing Src homology-2 (SH2) or phosphotyrosine-binding (PTB) domains, triggering diverse signaling cascades. Cytoplasmic proteins with SH2 or PTB domains could be effectors, proteins with enzymatic activity, or adaptors, proteins that mediate the activation of enzymes lacking these recognition web-sites. Some examples of signaling molecules are: phosphoinositide 3-kinase (PI3K), phospholipase C (PLC), development aspect receptor-binding protein (Grb), or the kinase Src, The key signaling pathways activated by RTK are: PI3K/Akt, Ras/Raf/ERK1/2 and signal transduction and activator of transcription (STAT) pathways (Figure 1).Cells 2014, three Figure 1. Major signal transduction pathways initiated by RTK.The PI3K/Akt pathway participates in apoptosis, migration and cell invasion manage [12]. This signaling cascade is initiated by PI3K activation as a result of RTK phosphorylation. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) generating phosphatidylinositol 3,4,5-triphosphate (PIP3), which mediates the activation on the serine/threonine kinase Akt (also known as protein kinase B). PIP3 induces Akt anchorage towards the cytosolic side of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20502316/ the plasma membrane, where the phosphoinositide-dependent protein kinase 1 (PDK1) and also the phosphoinositide-dependent protein kinase two (PDK2) activate Akt by phosphorylating threonine 308 and serine 473 residues, respectively. The when elusive PDK2, even so, has been lately identified as mammalian target of rapamycin (mTOR) within a rapamycin-insensitive complicated with rictor and Sin1 [13]. Upon phosphorylation, Akt is able to phosphorylate a plethora of substrates involved in cell cycle regulation, apoptosis, protein synthesis, glucose metabolism, and so forth [12,14]. A frequent alteration identified in glioblastoma that affects this signaling pathway is mutation or genetic loss from the tumor suppressor gene PTEN (Phosphatase and Tensin homologue deleted on chromosome ten), which encodes a dual-specificity protein phosphatase that catalyzes PIP3 dephosphorylation [15]. Therefore, PTEN is really a important damaging regulator of the PI3K/Akt pathway. About 20 to 40 of glioblastomas present PTEN mutational inactivation [16] and about 35 of glioblastomas suffer genetic loss because of promoter methylation [17]. The Ras/Raf/ERK1/2 pathway may be the principal mitogenic route initiated by RTK. This signaling pathway is trig.
