PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting

Cristiana Carniti, Carla Perego, Piera Mondellini, Marco Alessandro Pierotti, Italia Bongarzone

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

RET tyrosine kinase oncoproteins are potential targets for anticancer therapy. We show here that along with the inhibition of RET tyrosine phosphorylation, the pyrazolo-pyrimidine inhibitor PP1 induces RETMEN2A and RETMEN2B oncoprotein destruction. In fact, as a consequence of PP1 treatment, RET oncoproteins translocate from the outer limiting membrane to inner cellular compartments and are rapidly addressed to the degradative pathway. The cleavage of RET oncoproteins is associated with an impairment of RET mitogenic signaling pathways that causes a reversion of the oncogenic transformation and establishes a long-term cytostatic effect. By using specific inhibitors of both the proteosome and the lysosome, we assessed that PP1 targets RET oncoproteins to proteosomal, rather than lysosomal, degradation. In this context of studies, we interestingly demonstrated that RETMEN2A and RETMEN2B receptors are constitutively ubiquitinated and interact with the ubiquitin ligase c-Cbl. Moreover, PP1 does not modify these interactions, although it indeed causes RET dephosphorylation. Therefore, even if the degradative pathway stimulated by the inhibitor appears to be mediated by the proteosome, PP1 does not seem to enhance nor promote receptor ubiquitination. These observations lead us to favor two models for PP1-induced RET oncoprotein degradation: either PP1-mediated RET dephosphorylation per se targets the oncoproteins for destruction or alternatively, PP1 insertion in the RET ATP-binding pocket promotes a mechanism for fast stress-induced degradation. The use of PP1, which therefore acts as a degradation-inducing factor, may represent a promising new strategy to selectively target RET oncogenic products for destruction and holds promise for future medullary thyroid cancer therapy.

Original languageEnglish
Pages (from-to)2234-2243
Number of pages10
JournalCancer Research
Volume63
Issue number9
Publication statusPublished - May 1 2003

Fingerprint

Oncogene Proteins
Ubiquitination
Cytostatic Agents
Ligases
Ubiquitin
Lysosomes
Protein-Tyrosine Kinases
Tyrosine
Adenosine Triphosphate
Phosphorylation
Membranes
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting. / Carniti, Cristiana; Perego, Carla; Mondellini, Piera; Alessandro Pierotti, Marco; Bongarzone, Italia.

In: Cancer Research, Vol. 63, No. 9, 01.05.2003, p. 2234-2243.

Research output: Contribution to journalArticle

Carniti, Cristiana ; Perego, Carla ; Mondellini, Piera ; Alessandro Pierotti, Marco ; Bongarzone, Italia. / PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting. In: Cancer Research. 2003 ; Vol. 63, No. 9. pp. 2234-2243.
@article{6e7f44ce65f7447b8fe6be210a1112d8,
title = "PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting",
abstract = "RET tyrosine kinase oncoproteins are potential targets for anticancer therapy. We show here that along with the inhibition of RET tyrosine phosphorylation, the pyrazolo-pyrimidine inhibitor PP1 induces RETMEN2A and RETMEN2B oncoprotein destruction. In fact, as a consequence of PP1 treatment, RET oncoproteins translocate from the outer limiting membrane to inner cellular compartments and are rapidly addressed to the degradative pathway. The cleavage of RET oncoproteins is associated with an impairment of RET mitogenic signaling pathways that causes a reversion of the oncogenic transformation and establishes a long-term cytostatic effect. By using specific inhibitors of both the proteosome and the lysosome, we assessed that PP1 targets RET oncoproteins to proteosomal, rather than lysosomal, degradation. In this context of studies, we interestingly demonstrated that RETMEN2A and RETMEN2B receptors are constitutively ubiquitinated and interact with the ubiquitin ligase c-Cbl. Moreover, PP1 does not modify these interactions, although it indeed causes RET dephosphorylation. Therefore, even if the degradative pathway stimulated by the inhibitor appears to be mediated by the proteosome, PP1 does not seem to enhance nor promote receptor ubiquitination. These observations lead us to favor two models for PP1-induced RET oncoprotein degradation: either PP1-mediated RET dephosphorylation per se targets the oncoproteins for destruction or alternatively, PP1 insertion in the RET ATP-binding pocket promotes a mechanism for fast stress-induced degradation. The use of PP1, which therefore acts as a degradation-inducing factor, may represent a promising new strategy to selectively target RET oncogenic products for destruction and holds promise for future medullary thyroid cancer therapy.",
author = "Cristiana Carniti and Carla Perego and Piera Mondellini and {Alessandro Pierotti}, Marco and Italia Bongarzone",
year = "2003",
month = "5",
day = "1",
language = "English",
volume = "63",
pages = "2234--2243",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting

AU - Carniti, Cristiana

AU - Perego, Carla

AU - Mondellini, Piera

AU - Alessandro Pierotti, Marco

AU - Bongarzone, Italia

PY - 2003/5/1

Y1 - 2003/5/1

N2 - RET tyrosine kinase oncoproteins are potential targets for anticancer therapy. We show here that along with the inhibition of RET tyrosine phosphorylation, the pyrazolo-pyrimidine inhibitor PP1 induces RETMEN2A and RETMEN2B oncoprotein destruction. In fact, as a consequence of PP1 treatment, RET oncoproteins translocate from the outer limiting membrane to inner cellular compartments and are rapidly addressed to the degradative pathway. The cleavage of RET oncoproteins is associated with an impairment of RET mitogenic signaling pathways that causes a reversion of the oncogenic transformation and establishes a long-term cytostatic effect. By using specific inhibitors of both the proteosome and the lysosome, we assessed that PP1 targets RET oncoproteins to proteosomal, rather than lysosomal, degradation. In this context of studies, we interestingly demonstrated that RETMEN2A and RETMEN2B receptors are constitutively ubiquitinated and interact with the ubiquitin ligase c-Cbl. Moreover, PP1 does not modify these interactions, although it indeed causes RET dephosphorylation. Therefore, even if the degradative pathway stimulated by the inhibitor appears to be mediated by the proteosome, PP1 does not seem to enhance nor promote receptor ubiquitination. These observations lead us to favor two models for PP1-induced RET oncoprotein degradation: either PP1-mediated RET dephosphorylation per se targets the oncoproteins for destruction or alternatively, PP1 insertion in the RET ATP-binding pocket promotes a mechanism for fast stress-induced degradation. The use of PP1, which therefore acts as a degradation-inducing factor, may represent a promising new strategy to selectively target RET oncogenic products for destruction and holds promise for future medullary thyroid cancer therapy.

AB - RET tyrosine kinase oncoproteins are potential targets for anticancer therapy. We show here that along with the inhibition of RET tyrosine phosphorylation, the pyrazolo-pyrimidine inhibitor PP1 induces RETMEN2A and RETMEN2B oncoprotein destruction. In fact, as a consequence of PP1 treatment, RET oncoproteins translocate from the outer limiting membrane to inner cellular compartments and are rapidly addressed to the degradative pathway. The cleavage of RET oncoproteins is associated with an impairment of RET mitogenic signaling pathways that causes a reversion of the oncogenic transformation and establishes a long-term cytostatic effect. By using specific inhibitors of both the proteosome and the lysosome, we assessed that PP1 targets RET oncoproteins to proteosomal, rather than lysosomal, degradation. In this context of studies, we interestingly demonstrated that RETMEN2A and RETMEN2B receptors are constitutively ubiquitinated and interact with the ubiquitin ligase c-Cbl. Moreover, PP1 does not modify these interactions, although it indeed causes RET dephosphorylation. Therefore, even if the degradative pathway stimulated by the inhibitor appears to be mediated by the proteosome, PP1 does not seem to enhance nor promote receptor ubiquitination. These observations lead us to favor two models for PP1-induced RET oncoprotein degradation: either PP1-mediated RET dephosphorylation per se targets the oncoproteins for destruction or alternatively, PP1 insertion in the RET ATP-binding pocket promotes a mechanism for fast stress-induced degradation. The use of PP1, which therefore acts as a degradation-inducing factor, may represent a promising new strategy to selectively target RET oncogenic products for destruction and holds promise for future medullary thyroid cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=0037699063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037699063&partnerID=8YFLogxK

M3 - Article

VL - 63

SP - 2234

EP - 2243

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 9

ER -