Receptor tyrosine kinases are a class of enzyme-linked receptors that regulate cell growth, differentiation, metabolism, and survival. In contrast to G protein-coupled receptors, they mediate the effects of growth factors, insulin, and many other signaling molecules through intrinsic tyrosine kinase activity.
Structure and Activation
RTKs are single-pass transmembrane proteins with an extracellular ligand-binding domain, a single transmembrane helix, and a cytoplasmic region containing the tyrosine kinase domain. Fifty-eight RTKs in 20 subfamilies are encoded in the human genome, including the EGF receptor family, the insulin receptor family, the VEGF receptor family, and the FGF receptor family.
Ligand binding induces receptor dimerization, bringing the two kinase domains together. This allows trans-autophosphorylation of tyrosine residues in the activation loop of the kinase domain, stabilizing the active conformation and fully activating the kinase. Additional tyrosine residues in the juxtamembrane region and C-terminal tail become phosphorylated, creating docking sites for downstream signaling proteins.
The MAP Kinase Pathway
The MAP kinase cascade is a major signaling pathway downstream of RTKs. The activated RTK recruits the adaptor protein Grb2 through its SH2 domain, which binds to phosphotyrosine residues. Grb2 is constitutively associated with Sos, a guanine nucleotide exchange factor for Ras. Sos activates Ras by promoting GDP release and GTP binding.
Ras, a small GTPase, then recruits and activates the kinase Raf. Raf phosphorylates and activates MEK, which phosphorylates and activates ERK. ERK phosphorylates numerous cytoplasmic and nuclear targets, including transcription factors such as Elk-1 that regulate genes involved in cell proliferation and differentiation. ERK also phosphorylates upstream components, providing feedback regulation.
The PI3K-AKT Pathway
PI3K is recruited to activated RTKs either directly through its regulatory subunit or through adaptor proteins such as IRS-1. PI3K phosphorylates the membrane lipid phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate. PIP3 serves as a membrane docking site for proteins containing pleckstrin homology domains.
AKT, also called protein kinase B, is recruited to the membrane by binding PIP3, where it is activated by phosphorylation at threonine 308 by PDK1 and at serine 473 by mTORC2. AKT phosphorylates multiple targets that promote cell survival and growth. It inactivates the pro-apoptotic protein Bad, inhibits the FOXO transcription factors, activates mTORC1 through TSC2 inhibition, and promotes glucose uptake by stimulating GLUT4 translocation.
The JAK-STAT Pathway
Cytokine receptors lack intrinsic kinase activity but associate with JAK kinases. Ligand-induced dimerization brings JAKs into proximity, allowing trans-phosphorylation and activation. Activated JAKs phosphorylate tyrosine residues on the receptor cytoplasmic tail, creating docking sites for STAT transcription factors.
STAT proteins bind to the receptor through their SH2 domains and are phosphorylated by JAKs on a conserved tyrosine residue. Phosphorylated STATs dimerize through reciprocal SH2-phosphotyrosine interactions and translocate to the nucleus, where they bind to interferon-gamma-activated sequence elements in target gene promoters. STATs regulate genes involved in immune responses, inflammation, and cell survival.
Regulation and Signal Termination
RTK signaling is terminated by multiple mechanisms. Protein tyrosine phosphatases such as PTP1B dephosphorylate RTKs and their substrates, directly opposing kinase activity. The Ras-MAPK pathway is inhibited by RasGAP, which promotes GTP hydrolysis, and by ERK-mediated feedback phosphorylation of upstream components. The PI3K pathway is antagonized by PTEN, a phosphatase that dephosphorylates PIP3 to PIP3. Receptor internalization and degradation in lysosomes provides long-term downregulation. The E3 ubiquitin ligase Cbl promotes RTK ubiquitination and degradation.
Clinical Significance
RTK dysregulation is a hallmark of many cancers. EGFR is overexpressed or mutated in lung cancer, colorectal cancer, and glioblastoma. HER2 is amplified in breast cancer. VEGFR is targeted by anti-angiogenic drugs. Several targeted therapies inhibit RTK signaling. Imatinib targets the BCR-ABL fusion protein in chronic myeloid leukemia. Gefitinib and erlotinib inhibit EGFR. Trastuzumab is a monoclonal antibody against HER2. These drugs have transformed treatment of RTK-driven cancers.
