2015 journal article
Hyaluronidase Hyal1 Increases Tumor Cell Proliferation and Motility through Accelerated Vesicle Trafficking
Journal of Biological Chemistry, 290(21), 13144–13156.
MeSH headings : Adenocarcinoma / metabolism; Adenocarcinoma / pathology; Antigens, Neoplasm / metabolism; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Endocytosis / physiology; Endosomes / metabolism; Histone Acetyltransferases / metabolism; Humans; Hyaluronic Acid / metabolism; Hyaluronoglucosaminidase / metabolism; Male; Prostatic Neoplasms / metabolism; Prostatic Neoplasms / pathology; Protein Transport; Subcellular Fractions; Transferrin / metabolism; Transport Vesicles / metabolism; Tumor Cells, Cultured
TL;DR:
Overall, excess Hyal1 secretion accelerates endocytic vesicle trafficking in a substrate-dependent manner, promoting aggressive tumor cell behavior.
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www.jbc.org (publisher PDF)
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Added: December 21, 2020
Background: Hyal1 is a turnover enzyme for hyaluronan that accelerates metastatic cancer by increasing cell motility. Results: Hyal1-overexpressing cells have a higher rate of endocytosis that impacts cargo internalization and recycling. Conclusion: The higher rate of vesicle trafficking increases motility receptor function and nutrient uptake. Significance: This novel mechanism implicates Hyal1 trafficking in multiple signaling events during tumor progression. Hyaluronan (HA) turnover accelerates metastatic progression of prostate cancer in part by increasing rates of tumor cell proliferation and motility. To determine the mechanism, we overexpressed hyaluronidase 1 (Hyal1) as a fluorescent fusion protein and examined its impact on endocytosis and vesicular trafficking. Overexpression of Hyal1 led to increased rates of internalization of HA and the endocytic recycling marker transferrin. Live imaging of Hyal1, sucrose gradient centrifugation, and specific colocalization of Rab GTPases defined the subcellular distribution of Hyal1 as early and late endosomes, lysosomes, and recycling vesicles. Manipulation of vesicular trafficking by chemical inhibitors or with constitutively active and dominant negative Rab expression constructs caused atypical localization of Hyal1. Using the catalytically inactive point mutant Hyal1-E131Q, we found that enzymatic activity of Hyal1 was necessary for normal localization within the cell as Hyal1-E131Q was mainly detected within the endoplasmic reticulum. Expression of a HA-binding point mutant, Hyal1-Y202F, revealed that secretion of Hyal1 and concurrent reuptake from the extracellular space are critical for rapid HA internalization and cell proliferation. Overall, excess Hyal1 secretion accelerates endocytic vesicle trafficking in a substrate-dependent manner, promoting aggressive tumor cell behavior.