Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RET Tyrosine Kinase Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101648

Synonyms

 CDHF12;  CDHR16;  HSCR1;  MTC1;  MEN2;  PTC

Historical Background

RET (REarranged during Transfection) proto-oncogene, which locates on chromosome 10q11.2, encodes for a tyrosine kinase receptor that binds ligands of the GDNF (Glial-Derived Neurotrophic Factor) family (Maniè et al. 2001). It was first isolated in 1985 by Takahashi and coworkers (Takahashi et al. 1985) and later found rearranged in human thyroid papillary carcinoma (PTC) as a chimeric gene generated by fusion of RET tyrosine kinase with 5′ terminal region of a new gene called CCDC6, located on the same chromosome 10 (Grieco et al. 1990). RET is physiologically involved in the development of the central and peripheral nervous system, kidney, male germ cells, and thyroid calcitonin-secreting parafollicular C cells. In humans, loss-of-function mutations of RET cause congenital aganglionosis of the colon and impaired enteric nervous system formation, known as Hirschsprung’s disease, whereas RET gain-of-function mutations have been linked to sporadic and familiar medullary thyroid cancer (MTC), as part of multiple endocrine neoplasia type 2 syndromes (MEN2) (Santoro et al. 2002).

Structure and Signal Transduction

RET belongs to cadherin tyrosine kinase receptor (RTK) superfamily. The extracellular portion includes a cleavable signal peptide, four cadherin-related motifs, and a cysteine-rich domain; the transmembrane domain includes the hydrophobic portion of the protein, whereas the intracellular region has a juxtamembrane domain, a tyrosine kinase domain, divided in two subdomains by a kinase insert, and a C-terminal tail (Castellone and Santoro 2008). RET undergoes an alternative splicing that generates two protein isoforms of 1072 and 1114 amino acids (named RET9 and RET51). Upon ligand binding to the extracellular portion, through a GDNF coreceptor, RET protein dimerizes and induces the autophosphorylation of numerous tyrosine residues in the cytoplasmic domain (11 of which are maintained in RET/PTC proteins) with the consequent activation of signal transduction pathways (Santoro et al. 2004). Tyrosines 900 and 905 (Y900, Y905), located in the kinase loop, are essential for protein activation and binding to Grb7/Grb10 adaptors. Y981 is a docking site for c-Src. Y1015 binds to phospholipase Cγ and is important for kidney development and for RET/PTC oncogenic activity. Y1062 is the main docking site for numerous proteins including Shc, Enigma, IRS1/IRS2, FRS2, Rap1, and DOK1/DOK4/DOK5, leading to activation of Ras/ERK and phosphatidylinositol-3- kinase (PI3K)/AKT pathways that are crucial for the transforming activity of the oncogene as well as for RET function in embryonic development (Kondo et al. 2006; Castellone and Santoro 2008) (Fig. 1).
RET Tyrosine Kinase Receptor, Fig. 1

RET structure and signaling. RET is a transmembrane protein with four cadherin-related motifs, a cysteine-rich region, a hydrophobic transmembrane domain, a juxtamembrane domain, a tyrosine kinase domain (split by the kinase insert), and a C-terminal tail. The major phosphorylation sites and transduction pathways are drawn (see text for details)

Oncogenic Activation

Gain-of-function mutations of RET are involved in sporadic and familiar MTC, as part of the MEN2A and MEN2B syndromes. In 95% of MEN2B patients, a (M918T) mutation in the RET kinase domain correlates with increased ATP-binding affinity and formation of a more stable RET-ATP complex, switching the equilibrium toward the active conformation of the protein. In 98% of MEN2A and in 90% of FMTCs, mutations in the extracellular cysteine-rich domain of RET have been characterized, with increased dimerization and autophosphorylation of the protein and conversion of RET into a dominantly transforming oncogene (Santoro et al. 2004). Conversely, in PTC patients, RET undergoes chimeric rearrangements generating RET/PTC oncoproteins, originating from the in-frame fusion of the RET tyrosine kinase domain and COOH tail with the 5′ terminal end of heterologous genes possessing protein-protein interaction motifs that provide RET/PTC kinases with dimerizing interfaces, thereby resulting in ligand-independent autophosphorylation and activation of downstream signaling (Kawamoto et al. 2004, Kondo et al. 2006) (Fig. 2). Several studies have suggested that RET/PTC oncogenes can be causative in thyroid tumorigenesis and that they may represent an early genetic event in PTC development while they do not play a prominent role in thyroid tumor progression, as their prevalence in more aggressive and undifferentiated thyroid cancers is relatively low (Guerra et al. 2013). Interestingly, most of the RET partners are represented by genes with a tumor suppressor function, suggesting that RET/PTC rearrangements might cause a genetic double hit, inducing simultaneously the gain of RET oncogenic activity and the loss of RET partner gene (Kondo et al. 2006). To date, more than ten RET/PTC rearrangements have been described (Table 1) (Nikiforov 2002), RET/PTC1 and RET/PTC3 being the most common isoforms representing more than 90% of all rearrangements. RET/PTC3 is particularly frequent in people exposed to Chernobyl radiation contamination and in irradiated patients (Thomas et al. 1999; Williams 2008).
RET Tyrosine Kinase Receptor, Fig. 2

RET oncogenic activation.Red stars indicate the most common activating point mutations in RET: cysteine 634 (C634, mutated in MEN2A) and methionine 918 (M918, mutated in MEN2B). The position of the breakpoint occurring in PTC and causing the fusion of the RET kinase domain with heterologous genes possessing dimerization interfaces (RET/PTC chimeric proteins) is indicated with an arrow. Yellow circles mark the position of some critical RET phosphorylation tyrosine (see Fig. 1)

RET Tyrosine Kinase Receptor, Table 1

RET/PTC rearrangements identified in cancer

Oncogene

Donor gene

Rearrangements mechanisms and chromosomes involved

RET/PTC1

CCDC6

inv10(q11.2;q21)

RET/PTC2

PRKAR1A

t(10;17)(q11.2;q23)

RET/PTC3

NCOA4

inv10(q11.2;q10)

RET/PTC4

NCOA4

inv10(q11.2;q10)

RET/PTC5

GOLGA5

t(10;14)(q11.2;q32)

RET/PTC6

TRIM24

t(7;10)(q32–34;q11.2)

RET/PTC7

TRIM33

t(1;10)(p13;q11.2)

RET/PTC8

KTN1

t(10;14)(q11.2;q22.1)

RET/PTC9

RFG9

t(10;18)(q11.2;q21–22)

ELKS/RET

ELKS

t(10;12)(q11.2;p13.3)

PCM1/RET

PCM1

t(8;10)(q21–22;q11.2)

RFP-RET

TRIM27

t(6;10)(p21;q11.2)

HOOK3-RET

HOOK3

t(8;10)(p11.21;q11.2)

FGFR1OP-RET

FGFR1OP

t(6;10)(q27; q11)

BCR-RET

BCR

t(10;22)(q11;q11)

KIF5B-RET

KIF5B

inv10(p11.22;q11.21)

RET oncogenic activation has been investigated mainly in thyroid malignancies, although recent studies have suggested its involvement also in other malignancies. RET rearrangements with fibroblast growth factor receptor 1 oncogene partner (FGFR1OP) or BCR genes have been recently described in chronic myelomonocytic leukemia (CMML) and in acute myeloid leukemia (AML) secondary to primary myelofibrosis (Ballerini et al. 2012), whereas about 2% of non-small cell lung cancers (NSCLCs), predominantly nonsmokers and younger patients, have been discovered to be positive for RET fusion to kinesin family member 5B (KIF5B) gene (Kohno et al. 2012). Interestingly, the mutually exclusive nature of the RET fusions and other oncogenic alterations (EGFR, RAS, ALK) suggest that the KIF5B-RET rearrangement could work as driver mutation in lung cancer and could be related to a more severe prognosis. Recently, RET fusions with KIF5B (chromosome 10) and GOLGA5 (chromosome 14) have also been found in 3% of Spitz naevi and spitzoid melanomas (Wiesner et al. 2014), whereas RET/PTC1 rearrangements have been detected in 20% of primary peritoneal carcinomas (Flavin et al. 2009). Finally, RET overexpression has been described in breast and pancreatic cancers, in neuroblastoma, in seminoma, and in pituitary adenomas (Gattelli et al. 2013).

RET Targeting

RET targeting compounds belong mainly to two groups: monoclonal antibodies directed against the extracellular domain of RET and small-molecule kinase inhibitors (TKI) targeting the ATP-binding site of the tyrosine kinase domain (Schlumberger and Sherman 2009). Among the RET TKIs, vandetanib, sunitinib, sorafenib, and cabozantinib are in clinical trials in thyroid cancer patients (Santoro and Carlomagno 2006). In particular, vandetanib has demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC and has been approved by FDA for the treatment of patients with locally advanced or metastatic MTC (Wells et al. 2012). Nonetheless, recent identification of RET/PTC rearrangements in different malignancies other than thyroid cancers has an open possibility to target RET in several systems. In fact, following a rapid bench to bedside process, the identification of RET fusion in NSCLC patients has led to the initiation of a prospective phase II clinical study for advanced cancer patients using cabozantinib, a multi-tyrosine kinase inhibitor and potent RET inhibitor. Interestingly, all recently published preliminary results are encouraging as they show progression-free disease in all treated patients. Therefore, continuous improvement in understanding cancer pathogenesis as well as in the identification of molecular mechanisms of carcinogenesis will open the possibility to utilize RET inhibitors on a larger set of malignancies, as well as on patients that are not responsive to conventional treatments.

Summary

Since its isolation about 30 years ago, there has been significant progress in understanding the oncogenic effects exerted by RET tyrosine kinase receptor and in the identification of the intracellular molecules mediating its signal transduction and leading to Ras/BRAF/ERK and PI3K/AKT signaling pathways activation that are crucial for the formation of various cancer types. Recent studies have demonstrated that cancers in which RET mutations are causative events are highly dependent on this oncogene for their maintenance (oncogene addiction), as they can be treated by TKI (targeted therapy). The discovery that RET activation is found in a number of different malignancies suggests that the use of selective inhibitors that intercept RET kinase or downstream signaling could benefit a large group of cancer patients as well as could be tested in cancers where no driver mutations have been identified yet.

See Also

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Maria Domenica Castellone
    • 1
  • Mikko O. Laukkanen
    • 2
  1. 1.Institute of Experimental Endocrinology and Oncology (IEOS), CNRNaplesItaly
  2. 2.IRCCS SDNNaplesItaly