Oncogenic protein tyrosine kinases

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

doi:10.1007/s00018-004-4276-8

Cited by 81 publications

(19 citation statements)

References 69 publications

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“…It is well known that oncogenic RET proteins cause cell transformation by modifying intracellular signal Oncogenic potential of RET mutations N Miše et al transduction (Santoro et al, 2004;Marx, 2005). Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, for example, which regulates cellular survival (Besset et al, 2000), has been shown to be required for RET-mediated transformation (Segouffin-Cariou and Billaud, 2000;Drosten et al, 2004).…”

Section: Signaling Pathways Constitutively Activated By Different Retmentioning

confidence: 99%

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Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

et al. 2006

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Section: Signaling Pathways Constitutively Activated By Different Retmentioning

confidence: 99%

“…However, this phenotype is less frequent but clinically more aggressive (Santoro et al, 2004). Over 90% of all MEN 2B mutations occur in codon 918.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

et al. 2006

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“…These ligands bind RET through GPIanchored coreceptors (Santoro et al, 2004). RET genetic alterations are responsible for the occurrence of two thyroid malignancies, the medullary (MTC) and the papillary thyroid carcinomas (PTC).…”

Section: Introductionmentioning

confidence: 99%

“…Germline point mutations in RET cause MTC in the context of three related dominantly inherited tumor syndromes, multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B) and familial medullary thyroid carcinoma (FMTC). RET point mutations are also found in a fraction of sporadic MTCs (Santoro et al, 2004). PTC is the most common endocrine malignancy.…”

Section: Introductionmentioning

confidence: 99%

“…Both MTC-and PTC-associated RET genetic alterations have a gain-of-function effect, resulting in constitutive kinase activation and oncogenic conversion. Activation of RET either by ligand triggering or by oncogenic conversion initiates most of the signalling pathways activated by tyrosine kinases, such as the RAS/RAF/ERK and the PI3-K/Akt pathways (Santoro et al, 2004). Several groups have shown the central role of tyrosine 1062 of RET in signal transduction.…”

Section: Introductionmentioning

confidence: 99%

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RAI(ShcC/N-Shc)-dependent recruitment of GAB1 to RET oncoproteins potentiates PI3-K signalling in thyroid tumors

et al. 2005

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RAI, also named ShcC/N-Shc, one of the members of the Shc proteins family, is a substrate of the RET receptor tyrosine kinase. Here, we show that RAI forms a protein complex with both RET/MEN2A and RET/PTC oncoproteins. By coimmunoprecipitation, we found that RAI associates with the Grb2-associated binder1 (GAB1) adapter. This association is constitutive, but, in the presence of RET oncoproteins, both RAI and GAB1 are tyrosine-phosphorylated, and the stoichiometry of this interaction remarkably increases. Consequently, the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI-3K) is recruited to the complex, and its downstream effector Akt is activated. We show that human thyroid cancer cell lines derived from papillary or medullary thyroid carcinoma (PTC or MTC) carrying, respectively, RET/PTC and RET/MEN2A oncoproteins express RAI proteins. We also show that human PTC samples express higher levels of RAI, when compared to normal thyroid tissue. In thyroid cells expressing RET/PTC1, ectopic expression of RAI protects cells from apoptosis; on the other hand, the silencing of endogenous RAI by small inhibitory duplex RNAs in a PTC cell line that expresses endogenous RET/PTC1, increases the rate of spontaneous apoptosis. These data suggest that RAI is a critical substrate for RET oncoproteins in thyroid carcinomas.

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RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

et al. 2008

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Primary vesicoureteral reflux (pVUR) is a common, genetically heterogeneous congenital urinary tract abnormality in children. It causes urine to flow backward from the bladder to the ureter due to a developmental defect at the vesicoureteral junction, whose formation requires rearrangement during transformation (Ret)-mediated signaling pathways. To study the genetic causes of pVUR in Quebec patients, we used a sequencing-based candidate gene approach to screen the RET gene and found that 83 out of 118 pVUR patients are carriers of the rare A allele of single nucleotide polymorphism (SNP) rs1799939:G>A that results in a Gly691Ser mutation, a statistically significant increase in allelic frequency, that is absent at six flanking RET SNPs tested. Ser691 is a predicted phosphorylation site and our analysis of transfected cells showed that the Gly691Ser Ret mutant can efficiently interact and associate with a 75-80-kD tyrosine phosphorylated cellular protein, an event not seen with wild-type Ret. This interaction and/or the steric or electric hindrance created by phospho-Ser691 may interfere with the known regulatory functions of the normally phosphorylated phospho-Tyr687 and phospho-Ser696 on the cytoskeleton actin reorganization that are responsible for cell motility and morphology, which consequently may lead to the deficiency in ureteral development observed in pVUR. Our study demonstrates that the Ret Gly691Ser mutation is associated with pVUR and may be one of the genetic causes of this condition in the French-Canadian population in Quebec.

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Oncogenic protein tyrosine kinases

Cited by 81 publications

References 69 publications

Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

RAI(ShcC/N-Shc)-dependent recruitment of GAB1 to RET oncoproteins potentiates PI3-K signalling in thyroid tumors

RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

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