The tyrosine phosphatase PTPRO sensitizes colon cancer cells to
anti-EGFR therapy through activation of SRC-mediated EGFR
signaling

J 2014

The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling

ASBAH, Layka Abbasi, Iria VAZQUEZ, Loredana VECCHIONE, Eva BUDINSKÁ, Veerle DE VRIENDT et. al.

Basic information

Original name

The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling

Authors

ASBAH, Layka Abbasi (56 Belgium), Iria VAZQUEZ (56 Belgium), Loredana VECCHIONE (56 Belgium), Eva BUDINSKÁ (703 Slovakia, guarantor, belonging to the institution), Veerle DE VRIENDT (56 Belgium), Maria Francesca BAIETTI (56 Belgium), Mikhail STEKLOV (56 Belgium), Bart JACOBS (56 Belgium), Nicholas HOE (840 United States of America), Sharat SINGH (840 United States of America), Naga-Sailaja IMJETI (56 Belgium), Pascale ZIMMERMANN (56 Belgium), Anna SABLINA (56 Belgium) and Sabine TEJPAR (56 Belgium)

Edition

Oncotarget, New York, Impact Journals, 2014, 1949-2553

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 6.359

RIV identification code

RIV/00216224:14110/14:00078129

Organization unit

Faculty of Medicine

UT WoS

000348036500043

Keywords in English

EGFR; PTPRO; phosphatase; SRC kinase; EGFR inhibitor; colon cancer

Abstract

V originále

Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.

Citovat

ASBAH, Layka Abbasi, Iria VAZQUEZ, Loredana VECCHIONE, Eva BUDINSKÁ, Veerle DE VRIENDT, Maria Francesca BAIETTI, Mikhail STEKLOV, Bart JACOBS, Nicholas HOE, Sharat SINGH, Naga-Sailaja IMJETI, Pascale ZIMMERMANN, Anna SABLINA and Sabine TEJPAR. The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling. Oncotarget. New York: Impact Journals, 2014, vol. 5, No 20, p. 10070-10083. ISSN 1949-2553.

@article{1215467,
   author = {Asbah, Layka Abbasi and Vazquez, Iria and Vecchione, Loredana and Budinská, Eva and De Vriendt, Veerle and Baietti, Maria Francesca and Steklov, Mikhail and Jacobs, Bart and Hoe, Nicholas and Singh, Sharat and Imjeti, NagaandSailaja and Zimmermann, Pascale and Sablina, Anna and Tejpar, Sabine},
   article_location = {New York},
   article_number = {20},
   keywords = {EGFR; PTPRO; phosphatase; SRC kinase; EGFR inhibitor; colon cancer},
   language = {eng},
   issn = {1949-2553},
   journal = {Oncotarget},
   title = {The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling},
   volume = {5},
   year = {2014}
}

TY  - JOUR
ID  - 1215467
AU  - Asbah, Layka Abbasi - Vazquez, Iria - Vecchione, Loredana - Budinská, Eva - De Vriendt, Veerle - Baietti, Maria Francesca - Steklov, Mikhail - Jacobs, Bart - Hoe, Nicholas - Singh, Sharat - Imjeti, Naga-Sailaja - Zimmermann, Pascale - Sablina, Anna - Tejpar, Sabine
PY  - 2014
TI  - The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling
JF  - Oncotarget
VL  - 5
IS  - 20
SP  - 10070-10083
EP  - 10070-10083
PB  - Impact Journals
SN  - 19492553
KW  - EGFR
KW  - PTPRO
KW  - phosphatase
KW  - SRC kinase
KW  - EGFR inhibitor
KW  - colon cancer
N2  - Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.
ER  -

ASBAH, Layka Abbasi, Iria VAZQUEZ, Loredana VECCHIONE, Eva BUDINSKÁ, Veerle DE VRIENDT, Maria Francesca BAIETTI, Mikhail STEKLOV, Bart JACOBS, Nicholas HOE, Sharat SINGH, Naga-Sailaja IMJETI, Pascale ZIMMERMANN, Anna SABLINA and Sabine TEJPAR. The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling. \textit{Oncotarget}. New York: Impact Journals, 2014, vol.~5, No~20, p.~10070-10083. ISSN~1949-2553.

Detailed Information on Publication Record