A functional interaction between liprin-alpha1 and B56gamma regulatory subunit of protein phosphatase 2A supports tumor cell motility

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Journal: Communications Biology.
DOI : 10.1038/s42003-022-03989-3
Title : A functional interaction between liprin-α1 and B56γ regulatory subunit of protein phosphatase 2A supports tumor cell motility.

Scaffold liprin-alpha1 is required to assemble dynamic plasma membrane-associated platforms (PMAPs) at the front of migrating breast cancer cells, to promote protrusion and invasion. We show that the N-terminal region of liprin-alpha1 contains an LxxIxE motif interacting with B56 regulatory subunits of serine/threonine protein phosphatase 2A (PP2A). The specific interaction of B56gamma with liprin-alpha1 requires an intact motif, since two point mutations strongly reduce the interaction. B56gamma mediates the interaction of liprin-alpha1 with the heterotrimeric PP2A holoenzyme. Most B56gamma protein is recovered in the cytosolic fraction of invasive MDA-MB-231 breast cancer cells, where B56gamma is complexed with liprin-alpha1. While mutation of the short linear motif (SLiM) does not affect localization of liprin-alpha1 to PMAPs, localization of B56gamma at these sites specifically requires liprin-alpha1. Silencing of B56gamma or liprin-alpha1 inhibits to similar extent cell spreading on extracellular matrix, invasion, motility and lamellipodia dynamics in migrating MDA-MB-231 cells, suggesting that B56gamma-PP2A is a novel component of the PMAPs machinery regulating tumor cell motility. In this direction, inhibition of cell spreading by silencing liprin-alpha1 is not rescued by expression of B56gamma binding-defective liprin-alpha1 mutant. We propose that liprin-alpha1-mediated recruitment of PP2A via B56gamma regulates cell motility by controlling protrusion in migrating MDA-MB-231 cells.

请参阅以下文献：
期刊：通信生物学
DOI：10.1038/s42003-022-03989-3
标题：脂连蛋白-α1与蛋白磷酸酶2A的B56γ调节亚基之间的功能相互作用支持肿瘤细胞的迁移。
支架脂连蛋白-α1对于在迁移的乳腺癌细胞前端组装动态的质膜相关平台（PMAPs）至关重要，以促进突出和侵袭。研究发现，脂连蛋白-α1的N端区域含有与丝氨酸/苏氨酸蛋白磷酸酶2A（PP2A）的B56调节亚基相互作用的LxxIxE基序。B56gamma与脂连蛋白-α1的特异性相互作用需要一个完整的基序，因为两个点突变会显著降低这种相互作用。B56gamma介导脂连蛋白-α1与异源三聚体PP2A全酶的相互作用。大部分B56gamma蛋白在侵袭性MDA-MB-231乳腺癌细胞的细胞质部分中回收，其中B56gamma与脂连蛋白-α1形成复合物。尽管短线性基序（SLiM）的突变不会影响脂连蛋白-α1定位到PMAPs，但这些位点B56gamma的定位特别需要脂连蛋白-α1。B56gamma或脂连蛋白-α1的沉默抑制了类似程度的细胞在细胞外基质上的扩展、侵袭、迁移和伪足动力学，表明B56gamma-PP2A是PMAPs机器中调节肿瘤细胞迁移的新成分。在此方向上，通过沉默脂连蛋白-α1抑制细胞扩展的现象不能通过表达B56gamma结合缺陷的脂连蛋白-α1突变体得到挽救。我们提出，脂连蛋白-α1通过B56gamma介导的PP2A募集调节细胞迁移，通过控制迁移的MDA-MB-231细胞中的突出来发挥作用。