High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b.

High-molecular-weight hyaluronan, a major component of the extracellular matrix, is anti-oncogenic, whereas low-molecular-weight hyaluronan is pro-oncogenic, though the mechanisms underlying the size-dependent opposite bioactivities of hyaluronan remain uncertain. We show here that treatment with high-molecular-weight hyaluronan stimulates tumor-suppressive Hippo signaling in breast epithelial cells. Mechanistically, clustering of the CD44 extracellular ...
domain by high-molecular-weight hyaluronan leads to recruitment of the polarity-regulating kinase PAR1b by the CD44 intracellular domain, which results in disruption of the Hippo signaling-inhibitory PAR1b-MST complex. Once liberated from PAR1b, MST activates Hippo signaling. Conversely, low-molecular-weight hyaluronan, which is produced by hyaluronidase-mediated degradation of high-molecular-weight hyaluronan, inhibits Hippo signaling by competing with high-molecular-weight hyaluronan for CD44 binding. Triple-negative breast cancers with higher hyaluronidase-2 expression show poorer prognosis than those with lower hyaluronidase-2 expression. Consistently, decreased hyaluronidase-2 is associated with reduced tumorigenicity in a tumor xenograft model. Hence, perturbation of high-molecular-weight hyaluronan-mediated Hippo signaling activation contributes to cancer aggressiveness.
Mesh Terms:
Animals, Cell Adhesion Molecules, Cell Count, Cell Line, Tumor, Epithelial Cells, Extracellular Matrix, Female, GPI-Linked Proteins, HEK293 Cells, Heterografts, Humans, Hyaluronan Receptors, Hyaluronic Acid, Hyaluronoglucosaminidase, MAP Kinase Kinase Kinases, MCF-7 Cells, Mice, Inbred BALB C, Mice, Nude, Phosphorylation, Protein-Serine-Threonine Kinases, Signal Transduction, Triple Negative Breast Neoplasms
Dev. Cell
Date: Dec. 20, 2018
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