Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have explored CD44 (a hyaluronan (HA) receptor) interaction with a Na(+)-H(+) exchanger (NHE1) and hyaluronidase-2 (Hyal-2) during HA-induced cellular signaling in human breast tumor cells (MDA-MB-231 cell line). Immunological analyses demonstrate that CD44s (standard form) and two signaling molecules (NHE1 and Hyal-2) are closely associated in a complex in MDA-MB-231 cells. These three proteins are also significantly enriched in cholesterol and ganglioside-containing lipid rafts, characterized as caveolin and flotillin-rich plasma membrane microdomains. The binding of HA to CD44 activates Na(+)-H(+) exchange activity which, in turn, promotes intracellular acidification and creates an acidic extracellular matrix environment. This leads to Hyal-2-mediated HA catabolism, HA modification, and cysteine proteinase (cathepsin B) activation resulting in breast tumor cell invasion. In addition, we have observed the following: (i) HA/CD44-activated Rho kinase (ROK) mediates NHE1 phosphorylation and activity, and (ii) inhibition of ROK or NHE1 activity (by treating cells with a ROK inhibitor, Y27632, or NHE1 blocker, S-(N-ethyl-N-isopropyl) amiloride, respectively) blocks NHE1 phosphorylation/Na(+)-H(+) exchange activity, reduces intracellular acidification, eliminates the acidic environment in the extracellular matrix, and suppresses breast tumor-specific behaviors (e.g. Hyal-2-mediated HA modification, cathepsin B activation, and tumor cell invasion). Finally, down-regulation of CD44 or Hyal-2 expression (by treating cells with CD44 or Hyal-2-specific small interfering RNAs) not only inhibits HA-mediated CD44 signaling (e.g. ROK-mediated Na(+)-H(+) exchanger reaction and cellular pH changes) but also impairs oncogenic events (e.g. Hyal-2 activity, hyaluronan modification, cathepsin B activation, and tumor cell invasion). Taken together, our results suggest that CD44 interaction with a ROK-activated NHE1 (a Na(+)-H(+) exchanger) in cholesterol/ganglioside-containing lipid rafts plays a pivotal role in promoting intracellular/extracellular acidification required for Hyal-2 and cysteine proteinase-mediated matrix degradation and breast cancer progression.
 ...
PMID:CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. 1509 May 45

Cumulus cells surround the oocyte and regulate the production and assembly of the extracellular matrix (ECM) around the cumulus-oocyte complex for its timely interaction with sperm in the oviduct. We recently found that C-C chemokines such as CCL2, CCL7, and CCL9 are produced and stimulate integrin-mediated ECM assembly in the postovulatory cumulus to protect eggs and that prostaglandin E(2)-EP2 signaling in the cumulus cells facilitates fertilization by suppressing this chemokine signaling, which otherwise results in fertilization failure by preventing sperm penetration through the cumulus ECM. However, it remains unknown as to what mechanisms underlie chemokine-induced cumulus ECM assembly. Here we report that inhibition of EP2 signaling or addition of CCL7 augments RhoA activation and induces the surface accumulation of integrin and the contraction of cumulus cells. Enhanced surface accumulation of integrin then stimulates the formation and assembly of fibronectin fibrils as well as induces cumulus ECM resistance to hyaluronidase and sperm penetration. These changes in the cumulus ECM as well as cell contraction are relieved by the addition of Y27632 or blebbistatin. These results suggest that chemokines induce integrin engagement to the ECM and consequent ECM remodeling through the RhoA/Rho kinase/actomyosin pathway, making the cumulus ECM barrier resistant to sperm penetration. Based on these results, we propose that prostaglandin E(2)-EP2 signaling negatively regulates chemokine-induced Rho/ROCK signaling in cumulus cells for successful fertilization.
 ...
PMID:RhoA/Rho kinase signaling in the cumulus mediates extracellular matrix assembly. 1934 61