PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein

Amir Kedan; Nandini Verma; Ashish Saroha; Michal Shreberk-Shaked; Anna-Katharina Müller; Nishanth Ulhas Nair; Sima Lev

doi:10.1038/s41419-018-1005-z

PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein

Cell Death Dis. 2018 Sep 24;9(10):985. doi: 10.1038/s41419-018-1005-z.

Authors

Amir Kedan¹, Nandini Verma¹, Ashish Saroha¹, Michal Shreberk-Shaked¹, Anna-Katharina Müller¹, Nishanth Ulhas Nair², Sima Lev³

Affiliations

¹ Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
² Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA.
³ Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, 76100, Israel. sima.lev@weizmann.ac.il.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Apoptosis
Cell Line, Tumor
Focal Adhesion Kinase 1 / antagonists & inhibitors
Focal Adhesion Kinase 2 / antagonists & inhibitors
Focal Adhesion Kinase 2 / genetics
Focal Adhesion Kinase 2 / metabolism*
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
HEK293 Cells
Humans
Lithium Chloride / pharmacology
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / metabolism*
Proteolysis
Quinolones / pharmacology
Sulfones / pharmacology
Trans-Activators
Transcription Factors / metabolism*
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Transfection
Triple Negative Breast Neoplasms / metabolism*
Triple Negative Breast Neoplasms / pathology
Tumor Suppressor Proteins / metabolism*
YAP-Signaling Proteins

Substances

6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one
Adaptor Proteins, Signal Transducing
Protein Kinase Inhibitors
Quinolones
Sulfones
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Tumor Suppressor Proteins
WWTR1 protein, human
YAP-Signaling Proteins
YAP1 protein, human
LATS1 protein, human
LATS2 protein, human
Focal Adhesion Kinase 1
Focal Adhesion Kinase 2
PTK2 protein, human
PTK2B protein, human
Glycogen Synthase Kinase 3 beta
Protein Serine-Threonine Kinases
Lithium Chloride