Minireview: RET: Normal and Abnormal Functions

Santoro, Massimo; Melillo, Rosa Marina; Carlomagno, Francesca; Vecchio, Giancarlo; Fusco, Alfredo

doi:10.1210/en.2004-0922

Cited by 163 publications

(137 citation statements)

References 37 publications

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“…The RET activation complex comprises a soluble ligand of the glial cell line-derived neurotrophic factor (GDNF) family, a glycosyl-phosphatidylinositol membrane-anchored coreceptor of the GDNF family receptors a (GFRa) proteins, and RET itself (Airaksinen and Saarma, 2002). RET's downstream targets include the Ras/Erk kinase, PI3 kinase/Akt, p38MAP kinase, PLC-g, JNK, STAT, Erk5 and Src signaling pathways (Santoro et al, 2004;Arighi et al, 2005;Kodama et al, 2005). Autophosphorylation of tyrosine 1062, in the C-terminal tail, results in a phosphodependent-docking site for a number of SH2 or PTB domain containing proteins.…”

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confidence: 99%

RET ligand-induced internalization and its consequences for downstream signaling

2006

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RET is a receptor tyrosine kinase (RTK) with roles in cell growth, differentiation and survival. Ligand-induced activation of RET results in stimulation of multiple signal transduction pathways, including the MAP kinase/Erk and PI3 kinase/Akt pathways. However, the mechanisms governing receptor internalization and signal downregulation have not been explored. As other RTKs are internalized through the clathrin-coated pit pathway in a ligand-dependant manner, we have investigated whether RET is internalized through a similar process. Using a highly sensitive fluorescence resonance energy transfer (FRET)-based assay, we have shown that RET is internalized from the plasma membrane in a liganddependant manner that requires RET kinase activity as well as the GTPase activity of the clathrin-coated vesicle scission protein dynamin 2. Further, we have demonstrated that RET colocalizes with Rab5a, a marker of clathrin-coated vesicles and early endosomes, after internalization. Finally, we demonstrated that RET internalization is required for complete activation of Erk1/2, but not for activation of Akt signaling. Our data suggest that ligand-induced internalization of RET not only plays an overall role in downregulation and termination of signaling, but also functions to traffic RET to subcellular locations where it can fully activate certain downstream signaling pathways.

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confidence: 99%

RET ligand-induced internalization and its consequences for downstream signaling

2006

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“…Indeed, the biological functions of these proteins result from the coordinated activity of multiple kinase cascades, whose integrated signals control renal development, histogenesis of the enteric nervous system and, possibly, tumor formation (5,8,10). Our finding that RET/PTC3 and RET/MEN2B activate Erk8 suggests a role for this kinase in the transforming activity of RET-derived oncogenes and raises the possibility of a novel Erk8-dependent signaling pathway controlling RET biological functions.…”

Section: Discussionmentioning

confidence: 99%

“…In complex with four glycosylphosphatidylinositol-anchored coreceptors, GFR-␣ 1-4, the RET protein binds growth factors of the glial-derived neurotrophic factor family, mediating their intracellular signaling (4). As for other receptor tyrosine-kinases, ligand interaction triggers autophosphorylation of different RET intracellular tyrosine residues that work as docking sites for several adaptor and effector signaling molecules (5). Among such tyrosines, although Tyr 981 is a binding site for c-Src, Tyr 1062 has been shown to mediate the interactions with most of RET effectors and to be responsible for activation of the Ras/Erk, phosphatidylinositol 3-kinase/ Akt, Jnk, p38, and Erk5 signaling pathways (6).…”

Section: Mapmentioning

confidence: 99%

“…RET germline point mutations are in fact responsible for the three clinical subtypes of the multiple endocrine neoplasias type 2 (MEN2) syndrome, MEN2A, MEN2B, and familial medullary thyroid carcinoma (5). In addition, fusion of the intracellular kinase domain of RET with heterologous genes, caused by chromosomal inversions or translocations, generates the RET/PTC oncogenes, which represent the genetic hallmark of papillary thyroid carcinomas (PTC), accounting for more than 80 -90% of all thyroid carcinomas (9).…”

Section: Mapmentioning

confidence: 99%

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Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene

Iavarone

Acunzo

Carlomagno

et al. 2006

Journal of Biological Chemistry

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Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr 981 , a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr 981 -mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions. MAP3 kinases are a family of proline-directed serine/threonine kinases that play a central role in signal transduction in all eukaryotic cells, from yeast to humans (1). They coordinate signaling from a variety of extracellular and intracellular stimuli by acting as components of modular systems that involve other kinases and regulatory proteins. These stimuli induce specific phosphorylation on a conserved Thr-XaaTyr motif present in all MAP kinases, thereby inducing their activation. Consequently, these proteins transmit the signals to a vast array of cellular regulatory proteins including protein kinases, transcription factors, cytoskeletal proteins, and other enzymes (1).Erk8 is the last identified member of the MAP kinase family of proteins (2). Expressed in humans at high levels in the brain, kidney, and lung, its activity can be modulated by serum and c-Src (2). Although possessing a very typical MAP kinase domain, Erk8 also presents a peculiarly long C-terminal domain containing two putative SH3-binding sites (2). Information concerning its upstream activators, downstream effectors, and cellular functions is still extremely limited.RET is a typical trans-membrane receptor tyrosine-kinase, essential for the development of the sympathetic, parasympathetic, and enteric nervous system and of the kidney (3). In complex with four glycosylphosphatidylinositol-anchored coreceptors, GFR-␣ 1-4, the RET protein binds growth factors of the glial-derived neurotrophic factor family, mediating their intracellular signaling (4). As for other receptor tyrosine-kinases, ligand interaction triggers autophosphorylation of different RET intracellular tyrosine residues that work as docking sites for several adaptor and effector signaling molecules (5). Among such tyrosines, although Tyr 981 is a binding site...

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“…Approximately 15% of human cancers harbour activating RAS mutations (Malumbres and Barbacid, 2003). Similarly, increased RAS signalling might result from constitutive activation of receptor tyrosine kinases (RTKs) or deregulated activity of downstream transducers controlling RAS function, such as neurofibromin and SHP-2 (Cichowski and Jacks, 2001;Jerome et al, 2003;Bennasroune et al, 2004;Santoro et al, 2004;Tartaglia et al, 2004). Very recently, large-scale genomic screens have also detected mutations of BRAF in 66% of malignant melanomas and at a lower frequency in colorectal and ovarian cancers (Davies et al, 2002).…”

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confidence: 99%

Biochemical and molecular characterization of the novel BRAFV599Ins mutation detected in a classic papillary thyroid carcinoma

et al. 2006

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Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAF V600E , appeared virtually unique in this cancer type. Here, we report on the identification in a classic PTC of a novel BRAF mutation, namely a 1795GTT insertion, resulting in BRAF V599Ins , and describe its biochemical and molecular characterization. Kinase assays carried out on BRAF V599Ins and BRAF V600E revealed a three-to five-fold increase in the enzymatic activity of both mutants with respect to BRAF WT . Similarly, evaluation of BRAFinduced phosphorylation of MEK, MAPK and RSK revealed a significant MAPK cascade activation in cells expressing BRAF V599Ins or BRAF V600E , but not in cells expressing BRAF WT . Molecular dynamic simulations showed a destabilization of the inactive conformation of the enzyme in both BRAF V599Ins and BRAF V600E mutants, but not in BRAF WT . The analysis of the interaction energies inside the catalytic site allowed to demonstrate the presence of repulsive electrostatic forces acting on the activation loop and moving from inward to outward of the mutant enzymes. Finally, focus assays in NIH-3T3 cells confirmed a high transformation rate in the cells transfected either with BRAF V599Ins or BRAF V600E . In conclusion, this study demonstrated that BRAF V599Ins , as BRAF V600E , is a 'gain of function' mutation, characterized by a constitutive catalytic activation, which accounts for its causative role in the studied PTC.

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Minireview: RET: Normal and Abnormal Functions

Cited by 163 publications

References 37 publications

RET ligand-induced internalization and its consequences for downstream signaling

RET ligand-induced internalization and its consequences for downstream signaling

Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene

Biochemical and molecular characterization of the novel BRAFV599Ins mutation detected in a classic papillary thyroid carcinoma

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