Tumorigenic and adhesive properties of heparanase.
Tumorigenic and adhesive properties of heparanase.
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DOI：
10.1016/j.semcancer.2010.06.005
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发表时间：
2010-06
影响因子：
14.5
通讯作者：
Vlodavsky I
中科院分区：
文献类型：
--
作者：
Levy-Adam F;Ilan N;Vlodavsky I
乙酰肝素酶是一种内切-β-葡萄糖醛酸酶，其可能在低硫酸化位点切割硫酸乙酰肝素侧链，活性与癌症转移相关的细胞侵袭密切相关，这是结构修饰松动细胞外基质屏障的结果。此外，乙酰肝素酶发挥促粘附特性，通过膜硫酸乙酰肝素蛋白聚糖的聚集（即，多配体蛋白聚糖）和以硫酸乙酰肝素依赖性和非依赖性方式激活信号传导分子如Akt、Src、EGFR和Rac。无酶活性的乙酰肝素酶和与其底物结合结构域对应的肽激活信号级联不仅增加细胞粘附，而且促进癌细胞生长。这一概念得到了临床前和临床环境的支持，鼓励了抗乙酰肝素酶疗法的发展。在这里，我们总结了乙酰肝素酶研究的最新进展，强调其促肿瘤发生和促粘附特性的分子机制。亲粘附特性的乙酰肝素酶同系物，乙酰肝素酶2（Hpa 2），也进行了讨论。蛋白酶的酶活性非依赖性功能（即，基质金属蛋白酶）在细胞粘附和肿瘤进展的背景下讨论。总的来说，这些例子表明，酶的功能超出了酶的方面，从而显着扩大了功能蛋白质组的范围。还描述了与基质金属蛋白酶的串扰以及乙酰肝素酶在癌症以外的病理环境中的作用。
Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains presumably at sites of low sulfation, activity that is strongly implicated with cell invasion associated with cancer metastasis, a consequence of structural modification that loosens the extracellular matrix barrier. In addition, heparanase exerts pro-adhesive properties, mediated by clustering of membrane heparan sulfate proteoglycans (i.e., syndecans) and activation of signaling molecules such as Akt, Src, EGFR, and Rac in a heparan sulfate-dependent and -independent manner. Activation of signaling cascades by enzymatically inactive heparanase and by a peptide corresponding to its substrate binding domain not only increases cell adhesion but also facilitates cancer cell growth. This notion is supported by preclinical and clinical settings, encouraging the development of anti-heparanase therapeutics. Here we summarize recent progress in heparanase research emphasizing the molecular mechanisms that govern its pro-tumorigenic and pro-adhesive properties. Pro-adhesive properties of the heparanase homolog, heparanase 2 (Hpa2), are also discussed. Enzymatic activity-independent function of proteases (i.e., matrix metalloproteinases) is discussed in the context of cell adhesion and tumor progression. Collectively, these examples suggest that enzyme function exceeds beyond the enzymatic aspect, thus significantly expanding the scope of the functional proteome. Cross-talk with matrix metalloproteinases and the role of heparanase in pathological settings other than cancer is also described.
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影响因子：
6.4
作者：
BARNER, M;KRAMER, MD;VLODAVSKY, I
通讯作者：
VLODAVSKY, I
影响因子：
11.2
作者：
Finlay D;Howes A;Vuori K
通讯作者：
Vuori K
影响因子：
--
作者：
Casu B;Vlodavsky I;Sanderson RD
通讯作者：
Sanderson RD
影响因子：
4.8
作者：
Elkin, M;Ilan, N;Vlodavsky, I
通讯作者：
Vlodavsky, I
影响因子：
4.8
作者：
Barash, Uri;Cohen-Kaplan, Victoria;Vlodavsky, Israel
通讯作者：
Vlodavsky, Israel