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The RET Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

Abstract

The RET (REarranged during Transfection) gene encodes the tyrosine kinase membrane receptor (RET) for glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL). The human RET gene is located on the long arm of chromosome 10 (10q11.2). RET protein contains an N-terminal glycosylated extracellular portion, with four cadherin-like and one cysteine-rich domain, a central hydrophobic transmembrane segment, and a cytosolic domain that has the tyrosine kinase (TK) activity. RET activation is achieved through the formation of a ternary complex with GFLs and glycosylphosphatidylinositol (GPI)-anchored co-receptors of the GDNF receptor-α (GFRα) family. Upon binding to GFL-GFRα, RET protein undergoes dimerization and activation. RET loss-of-function mutations are found in developmental disorders such as Hirschsprung’s disease, characterized by the congenital absence of the enteric innervation, and congenital anomalies of the kidney or lower urinary tract. Gain-of-function mutations in RET are the driver events of the hereditary cancer syndromes named multiple endocrine neoplasia (MEN) type 2A and 2B. Gene rearrangements fusing the tyrosine kinase domain of RET with the N-terminal portion of heterologous proteins lead to the formation of chimeric oncoproteins endowed with constitutive catalytic activity in papillary thyroid carcinoma and other human malignancies. Finally, altered RET expression has been linked to several additional human neoplasms, including breast carcinoma.

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Abbreviations

aa:

Amino acid

ARTN:

Artemin

BCR:

Breakpoint cluster region

CAKUT:

Congenital anomalies of the kidney or lower urinary tract

CCHS:

Congenital central hypoventilation syndrome

Chip:

Chromatin immunoprecipitation

CLD:

Cadherin-like domain

CMML:

Chronic myelomonocytic leukemia

CNS:

Central nervous system

CRC:

Colorectal cancer

CRD:

Cysteine-rich domain

CREB:

Cyclic-AMP-response element binding protein

DA:

Dopaminergic

DNM2:

Dynamin 2 GTPase

ENS:

Enteric nervous system

ERE:

Estrogen-responsive elements

ET:

Endothelin

FDA:

Food and Drug Administration

FGFR1OP:

Fibroblast Growth Factor Receptor 1 Oncogenic Partner

GDNF:

Glial cell line-derived neurotrophic factor

GFL:

Glial cell line-derived neurotrophic factor family

GFRα:

GDNF receptor-α family

GPI:

Glycosylphosphatidylinositol

HMG:

High-mobility group

HSC:

Hematopoietic stem cell

HSCR:

Hirschsprung’s disease

JNK:

c-Jun N-terminal kinase

kbp:

Kilobase pair

KIF5B:

Kinesin family member 5B

LAR:

Leukocyte antigen related

LTβ:

Lymphotoxin β

LTβR:

LTβ receptor

MAPK:

Mitogen-activated protein kinases

MEN:

Multiple endocrine neoplasia

MEN2A:

Multiple endocrine neoplasia type 2A

MEN2B:

Multiple endocrine neoplasia type 2B

MTC:

Medullary thyroid carcinoma

NGF:

Nerve growth factor

NRTN:

Neurturin

NSCLC:

Non small cell lung cancer

OMIM:

Online Mendelian Inheritance in Men

PD:

Parkinson’s disease

PI3K:

Phosphatidylinositol-3-kinase

PKA:

Protein kinase A

PLCγ:

Phospholipase Cγ

PNI:

Perineural invasion

PP:

Peyer’s patches

PSPN:

Persephin

PTB:

Phosphotyrosine-binding domains

PTC:

Papillary thyroid carcinoma

PTP:

Protein tyrosine phosphatase(s)

RA:

Retinoic acid

RET:

REarranged during Transfection

RTK:

Receptor tyrosine kinase

SAXS:

Solution low-angle X-ray scattering

SCG:

Superior cervical ganglion

SCLC:

Small cell lung adenocarcinoma

SERM:

Selective estrogen receptor modulator

TGF-β:

Transforming growth factor β

TK:

Tyrosine kinase

TRPA1:

Transient receptor potential family of cation channels

TSS:

Transcription start site

UTR:

Untranslated regions

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Authors and Affiliations

  1. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita’ degli Studi di Napoli Federico II, via S. Pansini 5, 80131, Napoli, Italy

    Rosa Marina Melillo & Massimo Santoro

Authors
  1. Rosa Marina Melillo
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  2. Massimo Santoro
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Corresponding author

Correspondence to Massimo Santoro .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

Receptor at a glance: RET

Receptor at a glance: RET

Chromosome location

10q11.2

Gene Size (bp)

55 kb

Intron/exon numbers

20/21

mRNA size (5`, ORF, 3`)

7.0 kb; 6.0 kb; 4.5 kb; 3.9 kb

Amino acid number

1114 aa (RET51); 1106 aa (RET43); 1072 aa (RET9)

kDa

150 and 170 kDa

Posttranslational modifications

N- and O-glycosylation

Domains

4 cadherin-like domains (CLD) and 1 cysteine-rich region (CRD) in the extracellular region; 1 transmembrane domain and 1 tyrosine kinase domain (TKD) in the intracellular region split into two subdomains

Ligands

GDNF (glial cell line-derived neurotrophic factor); NRTN (neurturin); ARTN (artemin); PSPN (persephin)

Known dimerizing partners

TRKA; EDNRB

Pathways activated

RAS/RAF/MAP kinase; PI3K/AKT; PLCγ; SRC; STAT3

Tissues expressed

Peripheral and central nervous system; thyroid C-cells; adrenal medulla; developing ureteric bud; spermatogonia

Human diseases

Multiple Endocrine Neoplasia type 2 syndromes (MEN 2A, MEN 2B); sporadic medullary thyroid carcinoma; papillary thyroid carcinoma; lung adenocarcinoma; chronic myelomonocytic leukemia; Spitz tumor; breast and other carcinomas; Hirschsprung’s disease (colonic aganglionosis); congenital anomalies of the kidney or lower urinary tract (CAKUT)

Knockout mouse phenotype

Defective development of enteric nervous system; agenesis or dysgenesis of the kidney; defective spermatogenesis; defective Peyer’s patches; abnormal retinal function

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Melillo, R.M., Santoro, M. (2015). The RET Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_12

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