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Updated: Sep 24, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

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ZAP70 Activation Compensates for Loss of Class IA PI3K Isoforms Through Activation of the JAK-STAT3 Pathway

Melike Demir1, Onur Cizmecioglu1

  • 1Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.

Cancer Diagnosis & Prognosis
|May 9, 2022
PubMed
Abstract

Insights

Activated zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) drives cancer cell proliferation and resistance to phosphatidylinositol 3-kinase (PI3K) inhibitors by activating the JAK/STAT3 pathway.

Area of Science:

  • Cellular signaling and cancer biology
  • Molecular mechanisms of cancer resistance

Background:

  • The phosphatidylinositol 3-kinase (PI3K) pathway is crucial for cell proliferation and frequently deregulated in cancer.
  • Understanding resistance mechanisms to PI3K inhibition is vital for effective cancer therapy.

Purpose of the Study:

  • To identify tyrosine kinases contributing to resistance against PI3K silencing and inhibition.
  • To elucidate the role of ZAP70 in PI3K inhibitor resistance and cellular transformation.

Main Methods:

  • Utilized specific inhibitors (BYL719, KIN193) and genetic knock-out to mimic p110α/β inactivation.
  • Assessed cell viability using crystal violet staining and cellular transformation via soft-agar growth assays.

Main Results:

  • Activated zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) conferred resistance to PI3K inhibition.
  • ZAP70 activated the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) axis, mediating resistance.
  • Activated ZAP70 demonstrated significant transforming capability, promoting malignant phenotypes and acting as a potential tumor-initiating factor.

Conclusions:

  • ZAP70 is implicated as a driver of proliferation and transformation in untransformed cells.
  • ZAP70 plays a key role in mediating cancer cell resistance to PI3K inhibitors.
Keywords:
PI3KZAP70cell signalinggrowth resistancetyrosine kinases

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