Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization.
Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.
Lange
Katrin
K
Center for Biomedicine, Department of Clinical and Biological Sciences, University of Basel, Basel, Switzerland.
Kammerer
Martial
M
Hegi
Monika E
ME
Grotegut
Stefan
S
Dittmann
Antje
A
Huang
Wentao
W
Fluri
Erika
E
Yip
George W
GW
Götte
Martin
M
Ruiz
Christian
C
Orend
Gertraud
G
D000199:Actins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D022001:Focal Adhesions; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D044022:Receptor, Endothelin A / Q000378:metabolism / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D019063:Tenascin / Q000096:biosynthesis* / Q000378:metabolism
D000199:Actins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019063:Tenascin