Department of Medical and Clinical Genetics, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Oncogene. 2012 Jul 5;31(27):3277-86. doi: 10.1038/onc.2011.492. Epub 2011 Oct 24.
The phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, proliferation and survival, and are frequently affected in human cancer. PI3K is composed of a catalytic subunit, p110, and a regulatory subunit, p85. The PI3K catalytic subunit p110δ is encoded by PIK3CD and contains p85- and RAS-binding domains, and a kinase domain. Here we present an alternatively spliced PIK3CD transcript encoding a previously unknown protein, p37δ, and demonstrate that this protein is expressed in human ovarian and colorectal tumors. p37δ retains the p85-binding domain and a fraction of the RAS-binding domain, lacks the catalytic domain, and has a unique carboxyl-terminal region. In contrast to p110δ, which stabilizes p85, p37δ promoted p85 sequestering. Despite the truncated RAS-binding domain, p37δ bound to RAS and we found a strong positive correlation between the protein levels of p37δ and RAS. Overexpressing p37δ, but not p110δ, increased the proliferation and invasive properties of HEK-293 cells and mouse embryonic fibroblasts. Cells overexpressing p37δ showed a quicker phosphorylation response of AKT and ERK1/2 following serum stimulation. Ubiquitous expression of human p37δ in the fruit fly increased body size, DNA content and phosphorylated ERK1/2 levels. Thus, p37δ appears to be a new tumor-specific isoform of p110δ with growth-promoting properties.
磷脂酰肌醇 3-激酶（PI3Ks）调节细胞生长、增殖和存活，并且在人类癌症中经常受到影响。PI3K 由催化亚基 p110 和调节亚基 p85 组成。PI3K 催化亚基 p110δ 由 PIK3CD 编码，包含 p85 和 RAS 结合域以及激酶域。在这里，我们提出了一种编码先前未知蛋白 p37δ 的 PIK3CD 转录本的选择性剪接，并且证明该蛋白在人类卵巢和结直肠肿瘤中表达。p37δ 保留了 p85 结合域和一部分 RAS 结合域，缺乏催化域，并且具有独特的羧基末端区域。与稳定 p85 的 p110δ 相反，p37δ 促进了 p85 的隔离。尽管 RAS 结合域被截断，p37δ 仍与 RAS 结合，并且我们发现 p37δ 蛋白水平与 RAS 之间存在强烈的正相关。与过表达 p110δ 相比，过表达 p37δ 增加了 HEK-293 细胞和小鼠胚胎成纤维细胞的增殖和侵袭特性。过表达 p37δ 的细胞在血清刺激后 AKT 和 ERK1/2 的磷酸化反应更快。在果蝇中广泛表达人 p37δ 会增加体型、DNA 含量和磷酸化 ERK1/2 水平。因此，p37δ 似乎是具有促生长特性的 p110δ 的新肿瘤特异性同工型。
