The PI3K pathway is one of the most deregulated pathways in cancer, which is predominantly due to gain of function mutations or altered expression of the PI3KCA gene. This is codified by what is seen for the class I PI3K catalytic subunit p110α, a common feature of many cancers. The metastasis suppressor protein NM23-H1 (NME1), whose ability to suppress the metastasis activities of different tumors has been widely described and was previously reported to alter phosphatidylinositol signaling. Here, we show interaction of NM23-H1 with the p110α subunit and the functional consequence of this interaction. This interaction is predominantly localized at the plasma membrane with some signals seen in the cytoplasmic compartment. Analysis of NM23-H1 levels showed a negative correlation between NM23-H1 expression and Akt phosphorylation, the key marker of PI3K pathway activation. Investigating the functional consequence of this interaction using cell motility and clonogenicity assays showed that expression of NM23-H1 reversed the enhanced migration, invasion, adhesion, and filopodia structure formation in cells expressing the p110α catalytic subunit. A similar trend was seen in anchorage-independent assays. Notably, differential analyses using NM23-H1 mutants which lacked the enzymatic and metastasis suppressor activity, showed no detectable interaction between p110α and the NM23-H1 mutant proteins P96S, H118F, and S120G, as well as no dysregulation of the PI3K-AKT axis.

PI3K 通路是癌症中最失调的通路之一，这主要是由于功能获得突变或PI3KCA表达改变所致基因。这是由 I 类 PI3K 催化亚基 p110α 所见的编码，这是许多癌症的共同特征。转移抑制蛋白 NM23-H1 (NME1)，其抑制不同肿瘤转移活动的能力已被广泛描述，并且先前据报道可改变磷脂酰肌醇信号。在这里，我们展示了 NM23-H1 与 p110α 亚基的相互作用以及这种相互作用的功能后果。这种相互作用主要位于质膜，在细胞质隔室中可以看到一些信号。NM23-H1 水平分析显示 NM23-H1 表达与 Akt 磷酸化（PI3K 通路激活的关键标志物）之间呈负相关。使用细胞运动和克隆形成试验研究这种相互作用的功能结果表明NM23-H1逆转了表达 p110α 催化亚基的细胞中增强的迁移、侵袭、粘附和丝状伪足结构形成。在不依赖锚定的测定中观察到类似的趋势。值得注意的是，使用缺乏酶促和转移抑制活性的 NM23-H1 突变体的差异分析表明，p110α 与 NM23-H1 突变蛋白 P96S、H118F 和 S120G 之间没有可检测的相互作用，也没有 PI3K-AKT 轴的失调。