Abstract:
PTPRD, a well-established tumor suppressor gene, encodes the protein tyrosine phosphatase-type D. This protein consists of three immunoglobulin-like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer-associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer-associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan-binding pocket enhanced PTPRD\'s binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG-mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.
摘要:
PTPRD,一个成熟的抑癌基因,编码蛋白酪氨酸磷酸酶型D。该蛋白由三个免疫球蛋白样(Ig)结构域组成,四到八个纤连蛋白3型(FN)结构域,一个跨膜片段,和两个细胞质串联酪氨酸磷酸酶结构域。已知PTPRD具有各种癌症相关的点突变。虽然推测PTPRD通过胞内区域的酪氨酸磷酸酶活性作为肿瘤抑制因子调节细胞功能,其细胞外结构域(ECD)在癌症中的功能尚不清楚。在这项研究中,我们系统地检查了ECD内92个癌症相关点突变的影响.我们发现,这些突变中有69.6%(92个中的64个)抑制了总蛋白表达和/或质膜定位。值得注意的是,在最后一个FN结构域和跨膜片段之间的区域内的几乎所有突变(21个中的20个)影响蛋白质表达和/或定位,强调该区域对蛋白质稳定性的重要性。我们进一步发现,与糖胺聚糖结合口袋相邻的Ig结构域内的一些突变增强了PTPRD对硫酸乙酰肝素蛋白聚糖(HSPG)的结合能力。提出这种相互作用抑制磷酸酶活性。因此,我们的发现表明,HSPG介导的磷酸酶活性减弱可能通过PTPRD失调参与致瘤过程。