Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Center for Cell Dynamics, Institute of Basic Biomedical Sciences, Johns Hopkins University, Baltimore, MD, USA.
Nat Commun. 2024 Mar 23;15(1):2612. doi: 10.1038/s41467-024-46855-y.
Class IA phosphoinositide 3-kinase (PI3K) galvanizes fundamental cellular processes such as migration, proliferation, and differentiation. To enable these multifaceted roles, the catalytic subunit p110 utilizes the multi-domain, regulatory subunit p85 through its inter SH2 domain (iSH2). In cell migration, its product PI(3,4,5)P generates locomotive activity. While non-catalytic roles are also implicated, underlying mechanisms and their relationship to PI(3,4,5)P signaling remain elusive. Here, we report that a disordered region of iSH2 contains AP2 binding motifs which can trigger clathrin and dynamin-mediated endocytosis independent of PI3K catalytic activity. The AP2 binding motif mutants of p85 aberrantly accumulate at focal adhesions and increase both velocity and persistency in fibroblast migration. We thus propose the dual functionality of PI3K in the control of cell motility, catalytic and non-catalytic, arising distinctly from juxtaposed regions within iSH2.
IA 类磷酸肌醇 3-激酶 (PI3K) 激发了迁移、增殖和分化等基本细胞过程。为了实现这些多方面的作用，催化亚基 p110 通过其相互 SH2 结构域（iSH2）利用多结构域调节亚基 p85。在细胞迁移中，其产物 PI(3,4,5)P 产生运动活性。虽然也暗示了非催化作用，但潜在的机制及其与 PI(3,4,5)P 信号的关系仍然难以捉摸。在这里，我们报告说 iSH2 中的一个无序区域包含 AP2 结合基序，这些基序可以触发网格蛋白和发动蛋白介导的内吞作用，而不依赖于 PI3K 催化活性。p85 的 AP2 结合基序突变体异常积聚在黏着斑处，并增加成纤维细胞迁移的速度和持久性。因此，我们提出 PI3K 在控制细胞运动性方面的双重功能，即催化和非催化，明显来自 iSH2 内部毗邻的区域。
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