Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

Chiariello, Mario; Visconti, Roberta; Carlomagno, Francesca; Melillo, Rosa Marina; Bucci, Cecilia; Franciscis, Vittorio de; Fox, Gary M.; Jing, Shuqian; Coso, Omar A.; Gutkind, J. Silvio; Fusco, Alfredo; Santoro, Massimo

doi:10.1038/sj.onc.1201778

Cited by 108 publications

(68 citation statements)

References 53 publications

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“…To extend these studies and to objectively identify additional factors that are produced following oncoprotein expression, we compared parental PC CL3 thyroid cells and those expressing RP3 or the Shc signaling mutant RP3 Y588F using a rat gene array containing 10 000 cDNAs. The function of RET/PTC1 to signal mitogenesis is dependent on the phosphorylation of tyrosine 451 and the subsequent binding of the adaptor protein Shc (Chiariello et al, 1998;Salvatore et al, 2000). In our previous report, tyrosine 588 in RP3 corresponding to Tyr 451 in RET/PTC1 was required for the production of certain inflammatory cytokines including Gmcsf, Mcp1 and Kc/Groa (Russell et al, 2003).…”

Section: Rp3 Oncogene Expression Induces Il24 In Thyroid Cellsmentioning

confidence: 99%

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Shinohara

Rothstein

2004

Oncogene

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Thyroid cancers, like hematological malignancies, are commonly associated with chromosomal translocations leading to the formation of fusion proteins. Through altered signaling by fusion proteins, cell death and survival pathways are disrupted and the physiological balance of cell-cell communication may be lost. A consequence of this disruption is the release of factors by stressed cells that alert the host. One type of host response is leukocytic infiltration that may develop into chronic inflammation or autoimmune disease. Although inflammation can be associated with neoplastic tissue, the mechanism driving this process is largely unknown. Therefore, to address the mechanism of cancer inflammation we investigated the effects of an oncogene in a murine model system. A comprehensive genetic analysis revealed several soluble factors that were induced by RET/papillary thyroid carcinoma (PTC)3 gene expression including several proinflammatory cytokines, chemokines and immunologically relevant costimulatory molecules. Following a large genetic screen using RP3-expressing thyroid cells, we identified a highly abundant transcript and later identified it as interleukin 24 (Il24), a cytokine with diverse tumor suppressor and inflammatory activities. We show that RET/PTC3 induces Il24 expression in rat thyrocytes and that this expression is dependent on the signaling properties of its tyrosine kinase. Likewise, RET/PTC3 induces large amounts of Il24 following expression in murine thyrocytes, but its expression is dramatically reduced in poorly differentiated carcinomas, a finding that parallels the loss of RET/PTC3 expression. Consistent with its behavior as a tumor suppressor, the loss of Il24 coincided with the loss of RET/PTC3 in poorly differentiated mouse tumors. A functional role of Il24 in the autocrine growth/survival of RET/PTC3-expressing thyroid cells was identified helping to support its role in cellular transformation. These data suggest that the induction of Il24 by oncogenes may support tumor growth at the early stages of cancer.

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Section: Rp3 Oncogene Expression Induces Il24 In Thyroid Cellsmentioning

confidence: 99%

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Shinohara

Rothstein

2004

Oncogene

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“…The ability of RP1 to signal mitogenesis is strongly dependent upon the phosphorylation of tyrosine 451 (Tyr 1062 in c-RET and Tyr 588 in RP3) and the subsequent binding of SHC adaptor proteins (Chiariello et al, 1998;Salvatore et al, 2000). Mutation of this tyrosine to phenylalanine can abrogate SHC binding and subsequent signaling through the JNK, RAS/MAPK and PI3 K pathways (Hayashi et al, 2000).…”

Section: An Rp3 Signaling-deficient Mutant Abrogates Cytokine Synthesmentioning

confidence: 99%

Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors

et al. 2003

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Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-jB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr 588 ; an important protein-binding site for downstream signaling. Together, these studies implicate oncogeneinduced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.

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“…Earlier reports suggested that promoting the dimerization of Ret by ligand (Chiariello et al, 1998) or MEN2A-type point mutation (Asai et al, 1995;Santoro et al, 1995) activates its kinase activity. We examined whether UV would promote dimerization of Ret proteins as a potential mechanism for its activation and superactivation.…”

Section: Uv Irradiation Promotes Dimerization Of Retmentioning

confidence: 99%

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

Kato¹,

Iwashita

Takeda³

et al. 2000

MBoC

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The c-RET proto-oncogene encodes a receptor-type tyrosine kinase, and its mutations in the germ line are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B). Ret kinases are constitutively activated as a result of MEN2A mutations (Ret-MEN2A) or MEN2B mutations (Ret-MEN2B). Here we demonstrate that UV light (UV) irradiation induces superactivation of the constitutively activated Ret-MEN2A and Ret-MEN2B as well as activation of c-Ret. Before UV irradiation, small percentages of c-Ret (3-4%) and Ret-MEN2B (1-2%) and large percentages of Ret-MEN2A (30 -40%) were dimerized through disulfide bonds. These dimerized Ret proteins were preferentially autophosphorylated, suggesting a close relation between up-regulated kinase activity and disulfide bond-mediated dimerization of Ret proteins. We found that UV irradiation promotes the disulfide bond-mediated dimerization of the Ret proteins, in close association with activation and superactivation of Ret kinases. UV irradiation also induced dimerization and activation of the extracellular domain-deleted mutant Ret (Ret-PTC-1). Interestingly, the levels of basic kinase activity and dimerization of Ret-PTC-1-C376A, in which cysteine 376 in the tyrosine kinase domain of Ret-PTC-1 was replaced by alanine, were low and were not increased by UV irradiation. These results suggest that Ret-PTC-1 cysteine 376 is one of possibly multiple critical target amino acids of UV for Ret kinase activation. Overexpression of Cu/Zn superoxide dismutase in cells as a result of gene transfection prevented both the UVmediated promotion of dimerization and the superactivation of Ret-MEN2A kinase. These results suggest that the UV-induced free radicals in cells attack intracellular domains of Ret to dimerize the kinase proteins for superactivation.

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Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

Cited by 108 publications

References 53 publications

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors

Ultraviolet Light Induces Redox Reaction–mediated Dimerization and Superactivation of Oncogenic Ret Tyrosine Kinases

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