Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101-2795, USA.
J Biol Chem. 2010 Feb 19;285(8):5868-77. doi: 10.1074/jbc.M109.070318. Epub 2009 Dec 15.
The matricellular SPARC family member hevin (SPARC-like 1/SPARCL-1/SC1/Mast9) contributes to neural development and alters tumor progression in a range of mammalian models. The distribution of hevin in mouse tissues was reexamined with a novel monoclonal antibody that discriminates between hevin and its ortholog SPARC. We now report proteolysis of hevin in many tissues, with the most extensive processing in the brain. We demonstrate a cleavage site within the hevin sequence for the neural tissue proteinase ADAMTS4. Digestion of hevin by ADAMTS4 in vitro produced fragments similar to those present in brain lysates. Monoclonal antibodies revealed a SPARC-like fragment generated from hevin that was co-localized with ADAMTS4 in vivo. We show that proteolysis of hevin by ADAMTS4 in the mouse cerebellum is important for the normal development of this tissue. In conclusion, we have identified the fragmentation of hevin by ADAMTS4 in the mouse brain and propose that this specific proteolysis is integral to cell morphology and extracellular matrix deposition in the developing brain.
基质细胞衍生的 SPARC 家族成员 hevin（SPARC 样蛋白 1/SPARCL-1/SC1/Mast9）有助于神经发育，并改变多种哺乳动物模型中的肿瘤进展。我们使用一种新的单克隆抗体重新检查了 hevin 在小鼠组织中的分布，该抗体可区分 hevin 和其同源物 SPARC。我们现在报告了许多组织中 hevin 的蛋白水解，其中大脑中的处理最为广泛。我们在 hevin 序列中鉴定出一个用于神经组织蛋白酶 ADAMTS4 的裂解位点。ADAMTS4 在体外消化 hevin 产生的片段与脑组织裂解物中存在的片段相似。单克隆抗体揭示了源自 hevin 的 SPARC 样片段，该片段在体内与 ADAMTS4 共定位。我们表明，ADAMTS4 在小鼠小脑中的 hevin 蛋白水解对该组织的正常发育很重要。总之，我们已经确定了 ADAMTS4 在小鼠大脑中对 hevin 的片段化，并提出这种特定的蛋白水解是发育中大脑中细胞形态和细胞外基质沉积的重要组成部分。
