Within cell signaling, several classes of transmembrane receptors exist: G-protein receptors (GPCR), ion channel receptors and enzyme-linked receptors.

Enzyme-linked receptors have the particularity of carrying out the enzymatic activity themselves by the phosphorylation of residues, without the need for the intervention of a membrane effector. Capable of performing both ligand binding and transduction mechanisms on their own, they present two levels of activation: a cytosolic response with metabolic effects, and a nuclear response (mitotic activity of cell growth).

Enzyme-linked receptors are divided into:

• Tyrosine kinase receptors (EGFR, ERBB, FGFR, IGFR, M-CSFR, Trk, PDGFR, AXL, EPH-R, VEGFR...)
• Serine/threonine kinase receptors (ActR-II, Alk, BMPRII, TGF-βR, Akt/Rac ...)
• Guanylate cyclase-coupled receptors: these receptors contain intrinsic cyclase activity (ANP)
• Tyrosine-Kinase Associated Receptors: these receptors lack tyrosine kinase activity, and hence depend on associated cytoplasmic tyrosine kinases known as Janus kinases and related JAK-STAT pathway activation (IFN, IL…)
• Receptor-type protein tyrosine phosphatases (CD45, IA2, DEP-1; LAR…).

Receptor tyrosine kinases are a group of transmembrane proteins capable of receiving signals from the outside via their extracellular part to transmit them inside the cell and induce many cellular messages. They form families described according to the ligands that bind to their extracellular domain: peptide hormones that resemble each other in their structures such as insulin or IGF.

The intracytoplasmic tyrosine kinase domain is the most conserved part of the RTKs. It consists of two regions:

• a regulatory region (autophosphorylation site on the tyrosine amino acids)
• a catalytic region (which carries the kinase activation).

The kinase activity, resulting from autophosphorylation on the tyrosine residues in the catalytic domain, has no effect on the expression and localization of receptors on the cell surface. However, it remains crucial for the activation of transduction pathways and for the induction of cellular responses, such as survival, proliferation and differentiation (Hubbard et al., 2000).

The transmembrane domain is characterized by a hydrophobic sequence whose function is to anchor the receptor to the membrane.

At present, 58 receptors with tyrosine kinase activity have been identified. According to their structural organization, these receptors are grouped into 20 different families. These receptors have a fairly similar structure and activation mechanisms.

The extracellular part includes domains that allow the receptor to change its conformation to a nearby receptor by dimerization (immunoglobulin-like domains, fibronectin, cysteine-rich domains, leucine).

The ligand is now bound to two receptors, and the intracellular parts of the two receptors can interact, triggering the recruitment of cytosolic proteins and the initiation of autophosphorylation in the regulatory region.

Cytosolic proteins - second messengers - have specific structural motifs that allow them to be stabilized to fully perform their functions:

• SRC Homology (SH): allows interaction with phosphotyrosine of other proteins,
• Phosphotyrosine-Binding Domain (PTB): will bind to phosphorylated tyrosines,
• Pleckstrin Homology (PH): associates with membrane lipids and allows binding to the membrane.

When these proteins are phosphorylated, modifications inside the cell engage three possible activation pathways.

The most important cytosolic protein in this pathway is Growth Factor Receptor Binding 2 (GRB2). GRB2 has an SH2 domain that allows it to interact with the phospho-tyrosines of the receptor, as well as an SH3 domain, which allows it to interact with the SOS protein. The latter activates the RAS protein, which exchanges GDP for GTP. The phosphorylation cascade allows the phosphorylation of RAF, MAK (Mitogen Activating Kinase) and Mitogen-activated protein kinases (MAPK). The active MAPK enters the cell nucleus, activates the transcription factor Cfos (to intervene on the cell cycle) and phosphorylates TCF and SRF (to intervene on cell proliferation).

This pathway is the major pathway of cell survival. Recognition by specific cytosolic proteins with SH, PTB and PH domains. Major protein is composed of two subunits: P85 regulatory and P110 catalytic. P85 thanks to SH2 domain interacts with phosphorylated tyrosines. These interactions allow the activation of the P110 subunit, which modifies PIP2 into PIP3. PIP3 is recognized by cytosolic protein PDK, which acts on two protein kinases, PKC and AKT/PKB. AKT will in turn phosphorylate a wide variety of proteins, including mTOR, which activates or inhibits cell proliferation and survival.

Taking into account the complexity of the transduction cascades within a cell, it becomes obvious that deregulation of an RTK can have serious consequences on the immunological activity.

Receptors with tyrosine kinase activity are frequently deregulated and result in either increased kinase activity or constitutive kinase activity.

RTK-induced oncogenic transformation can be triggered by several mechanisms, including:

• chromosomal rearrangements,
• point mutations or deletions in the receptor,
• gene amplification.

In 1960, Nowell and Hungerford described the Philadelphia chromosome. This abnormality, the single most common chromosomal abnormality in lymphoblastic leukemia, was first interpreted as a deletion of chromosome 22, one of the smallest human chromosomes (1).

In 1970, Abelson and Rabstein worked on Moloney murine leukemia virus (M-MuLV) by injecting it to mice. Unexpectedly, they observed that instead of developing the typical M-MuLV-induced T-cell leukemia, one mouse developed acute B-cell leukemia (2). After virus isolation, both researchers noted that the DNA sequences of the virus were quite different from the original M-MuLV strain, and decided to name it Abelson murine leukemia virus (A-MuLV). Subsequent molecular cloning confirmed that A-MuLV arose from recombination between M-MuLV and a normal mouse gene, c-abl.

In 1973, Rowley resumes the work of Nowell. He demonstrated that the Philadelphia chromosome was not a deletion of chromosome 22, but rather a reciprocal translocation resulting in a longer chromosome 9 and a shorter chromosome 22 (3). This translocation consequently gives birth to the fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22.

In 1980, Witte et al made the connection between phosphorylation activity and the transforming activity of viruses that cause leukaemia. The first tyrosine kinase oncogene associated with human hematologic disease was just discovered; Bcr–Abl (4).

Mutations in RTKs can affect different components.

Thus, as early as 1989, Weiner et al analyzed the aggregation states of proto-oncogenes and oncogenic forms of neu-encoded protein (Neu) in rats. They concluded that a single mutation in the receptor at the transmembrane level or in cysteine-rich regions could lead to the activation of enzymatic domains of the receptor and the acquisition of an oncogenic power (5).

But point mutations can also lead to inhibition of kinase activity.

In 1988, Geissler et al, working on piebaldism - an autosomal disorder of melanocyte development – demonstrated that the disease resulted from mutations of the c-kit proto-oncogene (6). Four year later, Spritz et al. proved that kinase activity of the receptor was inhibited (7).

Many examples of RTKs overexpressed in cancer exist and have been listed.

As early as 1987, Slamon et al demonstrated the correlation of relapse of breast cancer with HER-2/neu oncogene amplification. Consequently, the gene amplification of Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) in breast cancer has a prognostic value (8).

Another example is the famous MET receptor.

Also working on understanding breast cancer, Beviglia et al. observed in 1997 the increased expression of MET in MDA-MB-231 cells. This overexpression suggests that the MET receptor is involved in the development and progression of epithelial tumors (9).

1. Nowell P C, Hungerford D A 1960 A minute chromosome in human chronic granulocytic leukemia. Journal of the National Cancer Institute 25: 85-109
2. Abelson, H.T. and Rabstein, L.S. (1970) Cancer Res. 30, 2213-2222
3. Rowley J D 1973 A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [Letter]. Nature 243: 290-293
4. Witte, O., Dasgupta, A. & Baltimore, D. Abelson murine leukaemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature 283, 826–831 (1980). https://doi.org/10.1038/283826a0
5. Weiner, D. B., Liu, J., Cohen, J. A., Williams, W. V., & Greene, M. I. (1989). A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature, 339(6221), 230–231. doi:10.1038/339230a0
6. Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988 Oct 7;55(1):185-92. doi: 10.1016/0092-8674(88)90020-7. PMID: 2458842.
7. Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. R A Spritz, L B Giebel, S A Holmes. Am J Hum Genet. 1992 Feb; 50(2): 261–269.
8. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177-82. doi: 10.1126/science.3798106. PMID: 3798106.
9. Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH. Expression of the c-met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer. 1997;74(3):301–9.