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Updated: Feb 4, 2026
Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein
Amir Kedan1, Nandini Verma1, Ashish Saroha1
1Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
Abstract:
The tumor suppressor Hippo pathway negatively regulates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to inhibit cell growth and control organ size, whereas activation of YAP and TAZ is implicated in tumorigenesis and cancer metastasis. Here, we report that the nonreceptor tyrosine kinase PYK2 positively regulates TAZ and YAP transcriptional activity in triple-negative breast cancer (TNBC). We found that inhibition of PYK2 expression or its kinase activity substantially affects the steady-state level of TAZ and markedly facilitates its proteasomal degradation. This effect was specific to PYK2 inhibition and was not obtained by inhibition of FAK. Destabilization of TAZ was associated with profound effect of PYK2 inhibition on cell growth at low-density concomitant with reduced expression of TAZ-target genes and induction of cell apoptosis. We further show that PYK2 enhances the tyrosine phosphorylation of both TAZ and LATS1/2 and concomitantly TAZ stability, and that PYK2 protein level correlates with the level of TAZ protein in primary breast tumors. Together these observations suggest that PYK2 is an important regulator of the Hippo pathway, and its tyrosine kinase activity has a striking effect on TAZ stabilization and activation in TNBC.
Insights
The nonreceptor tyrosine kinase PYK2 stabilizes TAZ and YAP, promoting triple-negative breast cancer (TNBC) growth. Inhibiting PYK2 leads to TAZ degradation, reducing cancer cell proliferation and inducing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The Hippo pathway, including YAP and TAZ, regulates cell growth and organ size.
- Aberrant YAP/TAZ activation is linked to tumorigenesis and metastasis, particularly in triple-negative breast cancer (TNBC).
- The role of specific kinases in regulating YAP/TAZ in TNBC remains an active area of research.
Purpose of the Study:
- To investigate the role of the nonreceptor tyrosine kinase PYK2 in regulating YAP and TAZ activity in TNBC.
- To determine if PYK2 influences TAZ stability and transcriptional activity.
- To explore the therapeutic potential of targeting PYK2 in TNBC.
Main Methods:
- Inhibition of PYK2 expression and kinase activity in TNBC cells.
- Assessment of TAZ and YAP protein levels and proteasomal degradation.
- Analysis of TAZ-target gene expression and cell apoptosis.
- Tyrosine phosphorylation assays for TAZ and LATS1/2.
- Correlation analysis of PYK2 and TAZ protein levels in patient tumors.
Main Results:
- PYK2 positively regulates TAZ and YAP transcriptional activity in TNBC.
- PYK2 inhibition leads to TAZ destabilization and proteasomal degradation, independent of FAK.
- Targeting PYK2 significantly reduces cell growth, downregulates TAZ-target genes, and induces apoptosis.
- PYK2 enhances tyrosine phosphorylation of TAZ and LATS1/2, promoting TAZ stability.
- PYK2 protein levels positively correlate with TAZ protein levels in primary breast tumors.
Conclusions:
- PYK2 is a key regulator of the Hippo pathway in TNBC.
- PYK2's kinase activity is crucial for TAZ stabilization and activation.
- Targeting PYK2 represents a potential therapeutic strategy for TNBC.
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