Receptor tyrosine kinases (RTKs) are essential components of signaling transduction that mediate cell-to-cell communication. The RTK family includes, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFRs), vascular endothelial growth factor receptors (VEGFR), Ephs (ephrin receptors), and the insulin receptor, etc. Many members of this family have emerged as key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism.
Growth factors or other locally released proteins binding induce receptor dimerization and autophosphorylation, which creates binding sites for several molecules with Src-Homology 2 (SH2) or phosphotyrosine-binding (PTB) domains. This allows membrane recuitment of Grb2 (directly or through Shc) and Sos, causing activation of Ras, Raf, MEK, and ERKs.
Other key recruited molecules are PLC, which becomes phosphorylated and activated, and PI3K, which is brought to its substrates at the membrane. PI3K produces PIP3 at the plasma membrane, leading to membrane localization and activation of PDK1 and PKB. PKB promotes cell survival through at least three targets: Mdm2, BAD, and FoxO family transcription factors.
PDK1 and PKB also activate the TOR kinase, which additionally responds to nutrients, and thereby increases translation of mRNAs, especially those with oligopyrimidine tracts or secondary structure in the 5' UTR. ERK activation induces immediate early genes such as fos and myc. Fos and Myc contribute to transcription complexes that, along with the CREB family, induce secondary changes in transcription. A key response for cell-cycle induction is thought to be increased cyclin D1 transcription.
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