High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b
| Autor: | Masanori Hatakeyama, Naoko Murata-Kamiya, Takuya Ooki, Weida Wu, Atsushi Takahashi-Kanemitsu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Hyaluronoglucosaminidase
Mice Nude Cell Count Triple Negative Breast Neoplasms Protein Serine-Threonine Kinases GPI-Linked Proteins General Biochemistry Genetics and Molecular Biology Extracellular matrix 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Cell density Extracellular Animals Humans Hippo Signaling Pathway Hyaluronic Acid Phosphorylation Molecular Biology 030304 developmental biology 0303 health sciences Hippo signaling pathway Mice Inbred BALB C biology Kinase CD44 Epithelial Cells Cell Biology MAP Kinase Kinase Kinases Cell biology Extracellular Matrix HEK293 Cells Hyaluronan Receptors chemistry Hippo signaling biology.protein MCF-7 Cells Heterografts Female Growth inhibition Cell Adhesion Molecules 030217 neurology & neurosurgery Developmental Biology Signal Transduction |
| Zdroj: | Developmental cell. 49(4) |
| ISSN: | 1878-1551 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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