How does tyrosine kinase receptors work

The phosphorylation of tyrosines on the receptor tails triggers the assembly of an intracellular signaling complex on the tails. The newly phosphorylated tyrosines serve as binding sites for signaling proteins that then pass the message on to yet other proteins. An important protein that is subsequently activated by the signaling complexes on the receptor tyrosine kinases is called Ras. The Ras protein is a monomeric guanine nucleotide binding protein that is associated with the cytosolic face of the plasma membrane in fact, it is a lot like the alpha subunit of trimeric G-proteins.

When a signal arrives at the receptor tyrosine kinase, the receptor monomers come together and phosphorylate each others' tyrosines, triggering the assembly of a complex of proteins on the cytoplasmic tail of the receptor.

This activates the Ras. Activated Ras triggers a phosphorylation cascade of three protein kinases, which relay and distribute the signal.

Curr Opin Cell Biol — Annu Rev Biochem — Nat Rev Genet 5: — Trends Cell Biol — Role in EGF receptor-mediated tyrosine phosphorylation. Exp Cell Res — Cold Spring Harb Perspect Biol 5: a J Cell Sci — Traffic 7: — Traffic — PLoS One 8: e Consequences on nitric oxide production from endothelial cells. EMBO J — Arterioscler Thromb Vasc Biol — PLoS One 7: e J Neurosci — Mol Biol Cell — BMC Cell Biol Cell Biosci 2: Cell 45— Hum Pathol — Hepatology 15— J Cell Biochem — Discov Med — PLoS One 6: e Biochem Biophys Res Commun — Nucleic Acids Res D— Annu Rev Pathol 3: — N Engl J Med — Nat Rev Cancer — Lab Invest — J Gen Physiol 8: — Plos One 7: e Wound Repair Regen — Angiogenesis — Nat Rev Cancer 5: — Oncol Rep 7: — Eur J Cancer 37 Suppl 4: S9— Br J Cancer — J Natl Cancer Inst Monogr — Nat Rev Cancer 7: — Clin Cancer Res — J Clin Oncol — Circulation These proteins have a particular domain — called SH2 — that binds to phosphorylated tyrosines in the cytoplasmic RTK receptor tails.

More than one SH2-containing protein can bind at the same time to an activated RTK, allowing simultaneous activation of multiple intracellular signaling pathways. Ultimately, RTK activation brings about changes in gene transcription.

Signaling becomes complex as signals travel from the membrane to the nucleus, due to crosstalk between intermediates in various signaling pathways in the cell Figure 1. Figure 1: RTK activation involves the joining together and phosphorylation of proteins.

On the left, an unactivated RTK receptor pink encounters a ligand red. Upon binding, the receptor forms a complex of proteins that phosphorylate each other. In turn, this phosphorylation affects other proteins in the cell that change gene transcription not shown. Figure Detail. One of the most common intracellular signaling pathways triggered by RTKs is known as the mitogen-activated protein MAP kinase cascade , because it involves three serine-threonine kinases.

The pathway starts with the activation of Ras , a small G protein anchored to the plasma membrane. In its inactive state, Ras is bound to GDP. Each of the three kinases in this cascade then activates the next by phosphorylating it.

Because all three kinases in this pathway phosphorylate multiple substrates, the initial signal is amplified at each step. Then, the final enzyme in the pathway phosphorylates transcription regulators, leading to a change in gene transcription Figure 2.

Many growth factors, including nerve growth factor and platelet-derived growth factor, use this pathway. For example, insulin-like growth factor receptors activate the enzyme phosphoinositide 3-kinase, which phosphorylates inositol phospholipids in the cell membrane, leading in turn to a protein kinase cascade distinct from the MAP kinase cascade that relays the signal to the nucleus. Other RTKs use a more direct route to the nucleus.

Transcriptional regulators known as STAT proteins, an acronym for signal transducers and activators of transcription, bind to the phosphorylated tyrosines in the receptors for cytokines and some hormones. In normal biology, the presence of EGF ligands activates wild-type EGF receptor through the formation of an asymmetric dimer between two receptor molecules [ 9 ].

Therefore, for this variant, EGFR signaling can be activated in a ligand independent manner. Constitutive autocrine activation might lead to clonal expansion and tumor formation Fig. RTK autocrine loop may work synergistically with other autocrine growth pathway and drive tumor development. Autocrine pathways could act as a rational target for cancer therapy [ ]. For example, microRNAa promotes metastasis by directly regulating EPH4A-mediated epithelial-mesenchymal transition and adhesion in hepatocellular carcinoma [ ].

Moreover, microRNAs could function as potential prognostic markers and assist in patient stratification. An improved understanding of microRNAs involved in RTK signaling may have future implications in cancer detection, therapy and prognosis. Several notable advances have been made during the last decade in the recognition of the importance of tumor microenvironment, especially tumor vasculature and tumor stroma [ ].

Members of the Eph receptor family mediate cell-cell interaction in tumor stroma and tumor vasculature [ ]. Macrophages function as key cellular components of tumor microenvironment. AXL is highly expressed within tumor associated macrophages where AXL may promote immunosuppressive and pre-neoplasia phenotypes [ ]. RET and GFRA1 have been shown to be expressed in stromal cells of the bone marrow microenvironment and implicated in the development of acute myeloid leukemias [ ].

As such, these RTKs represent attractive potential targets for drug design. Many AXL inhibitors have been detected and are efficacious in preclinical studies against cancer [ ]. The activity of RTKs must be tightly regulated and properly balanced in order to mediate their normal cellular activities and physiological processes.

MIG6 has been described to be mutated in different human cancers [ , ]. MIG6 expression is also downregulated or silenced in skin, breast, pancreatic and ovarian carcinomas [ , ]. Loss of Errfi1 in mice leads to abnormal activation of EGFR signaling and is associated with a high incidence of neoplastic lesions [ ]. MIG6 contains two functional regions, termed segments 1 and 2 which are 77 amino acids in total [ ].

The C-lobe is less accessible by MIG6 in configurations that more strongly favor formation of asymmetric dimers [ 32 ]. Since RTKs play crucial roles in cancer development, targeting oncogenic driver mutations of RTKs has revolutionized the treatment of cancer patients. Above, we touched on how targeted therapies are deployed in specific clinical scenarios for patients whose tumors harbor oncogenic RTK variants. However, a detailed review of all RTK inhibitors in the treatment of human tumors is beyond the scope of this manuscript.

In brief, many small-molecule inhibitors have been developed for treating cancers and other diseases caused by driver mutations within RTKs. In addition, the US FDA has approved many monoclonal antibodies that interfere with RTK activation, including cetuximab in lung cancer [ ], panitumumab in colon cancer [ ], cetuximab in head and neck cancer [ ], trastuzumab and pertuzumab in breast cancer [ , ]. Overall, the development and routine clinical implementation of agents TKIs and monoclonal antibodies targeting RTKs has heralded the new age of precision cancer medicine.

Despite these advancements, acquired resistance to targeted therapies inevitably develops [ 40 , ]. Acquired resistance can occur through either acquired genomic alterations [ , ] or activation of critical signaling pathways [ , , ]. Novel approaches have been shown to effectively overcome acquired resistance, including the development of second-generation [ , ] and third-generation inhibitors [ , ] and the combinational use of TKIs with monoclonal antibodies against the same target [ ].

Our understanding of RTK signaling has advanced dramatically in the past two decades. Studies of RTKs have provided fundamental insight into how this protein family functions and how to develop targeted therapeutics. However, much work is still required to fully understand all members of the RTK family. An improved understanding of RTK signaling pathways will provide a strong foundation on which improvements to patient care can be made.

An integrated approach, combining genetic, cellular, biochemical, and structural modeling techniques, may offer the most complete view yet of this critical family of protein tyrosine kinases. The protein kinase complement of the human genome. The protein tyrosine kinase family of the human genome.

Hubbard SR. Structural analysis of receptor tyrosine kinases. Prog Biophys Mol Biol. Cancer genome landscapes. Schlessinger J.

Cell signaling by receptor tyrosine kinases. Lemmon MA, Schlessinger J. SH2 domains, interaction modules and cellular wiring.

Trends Cell Biol. Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.

Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Mol Cell. Spatial control of EGF receptor activation by reversible dimerization on living cells.

Biochem J. J Biol Chem. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Structural interactions of fibroblast growth factor receptor with its ligands. An open-and-shut case? Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.

Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Huse M, Kuriyan J. The conformational plasticity of protein kinases. Regulation of protein kinases; controlling activity through activation segment conformation. Structural basis for the autoinhibition and STI inhibition of c-kit tyrosine kinase.

The juxtamembrane region of the EGF receptor functions as an activation domain. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.

Docking proteins. FEBS J. Ostman A, Bohmer FD. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum Mol Genet. Kinase mutations in human disease: interpreting genotype-phenotype relationships. Nat Rev Genet. Medves S, Demoulin JB. Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.

J Cell Mol Med. Mechanistic insights into the activation of oncogenic forms of EGF receptor. Nat Struct Mol Biol. Epidermal growth factor receptor mutations in lung cancer. Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.

Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer EURTAC : a multicentre, open-label, randomised phase 3 trial.

Lancet Oncol. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor WJTOG : an open label, randomised phase 3 trial.

Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. PubMed Article Google Scholar. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

PLoS Med. Neuropathol Appl Neurobiol. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study Br J Cancer.