Fluid shear stress activates YAP1 to promote cancer cell motility

Hyun Jung Lee; Miguel F Diaz; Katherine M Price; Joyce A Ozuna; Songlin Zhang; Eva M Sevick-Muraca; John P Hagan; Pamela L Wenzel

doi:10.1038/ncomms14122

Fluid shear stress activates YAP1 to promote cancer cell motility

Nat Commun. 2017 Jan 18:8:14122. doi: 10.1038/ncomms14122.

Authors

Hyun Jung Lee^{1

2}, Miguel F Diaz^{1

2}, Katherine M Price³, Joyce A Ozuna³, Songlin Zhang⁴, Eva M Sevick-Muraca⁵, John P Hagan⁶, Pamela L Wenzel^{1

2}

Affiliations

¹ Children's Regenerative Medicine Program, Department of Pediatric Surgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
² Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
³ Department of BioSciences, Rice University, Houston, Texas 77030, USA.
⁴ Department of Pathology, The University of Texas Medical School, Houston, Texas 77030, USA.
⁵ Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
⁶ Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Abstract

Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1-TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK-LIMK-cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actin Depolymerizing Factors / genetics
Actin Depolymerizing Factors / metabolism
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Line, Tumor
Cell Movement*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Extracellular Fluid / chemistry*
Extracellular Fluid / metabolism
Humans
Lim Kinases / genetics
Lim Kinases / metabolism
Lymphatic Vessels / chemistry
Lymphatic Vessels / metabolism
Male
Mechanotransduction, Cellular
Mice
Mice, Nude
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / physiopathology*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Signal Transduction
Stress, Mechanical*
TEA Domain Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism
YAP-Signaling Proteins

Substances

Actin Depolymerizing Factors
Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Nuclear Proteins
Phosphoproteins
TEA Domain Transcription Factors
TEAD1 protein, human
TEAD2 protein, human
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
LIMK1 protein, human
Lim Kinases

Grants and funding

K01 DK092365/DK/NIDDK NIH HHS/United States