Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Biol Open. 2022 Jul 15;11(7). doi: 10.1242/bio.059024. Epub 2022 Jul 25.
Actin-based protrusions called cytonemes are reported to function in cell communication by supporting events such as morphogen gradient establishment and pattern formation. Despite the crucial roles of cytonemes in cell signaling, the molecular mechanism for cytoneme establishment remains elusive. In this study, we showed that the leukocyte common antigen-related (LAR) receptor protein tyrosine phosphatase plays an important role in cytoneme-like protrusion formation. Overexpression of LAR in HEK293T cells induced the formation of actin-based protrusions, some of which exceeded 200 µm in length and displayed a complex morphology with branches. Upon focusing on the regulation of LAR dimerization or clustering and the resulting regulatory effects on LAR phosphatase activity, we found that longer and more branched protrusions were formed when LAR dimerization was artificially induced and when heparan sulfate was applied. Interestingly, although the truncated form of LAR lacking phosphatase-related domains promoted protrusion formation, the phosphatase-inactive forms did not show clear changes, suggesting that LAR dimerization triggers the formation of cytoneme-like protrusions in a phosphatase-independent manner. Our results thus emphasize the importance of LAR and its dimerization in cell signaling. This article has an associated First Person interview with the first author of the paper.
细胞丝状伪足是一种由肌动蛋白构成的突起，据报道其在细胞通讯中发挥作用，支持形态发生素梯度建立和模式形成等事件。尽管细胞丝状伪足在细胞信号转导中起着至关重要的作用，但建立细胞丝状伪足的分子机制仍难以捉摸。在本研究中，我们表明白细胞共同抗原相关（LAR）受体蛋白酪氨酸磷酸酶在细胞丝状伪足样突起的形成中发挥重要作用。在 HEK293T 细胞中过表达 LAR 会诱导肌动蛋白为基础的突起的形成，其中一些突起超过 200 µm 长，并呈现出具有分支的复杂形态。当我们专注于调节 LAR 二聚化或聚集以及由此对 LAR 磷酸酶活性的调节作用时，我们发现当人工诱导 LAR 二聚化和应用肝素硫酸盐时，会形成更长和更多分支的突起。有趣的是，尽管缺乏磷酸酶相关结构域的 LAR 截断形式促进了突起的形成，但无活性的磷酸酶形式没有显示出明显的变化，这表明 LAR 二聚化以一种独立于磷酸酶的方式触发了细胞丝状伪足样突起的形成。因此，我们的结果强调了 LAR 及其二聚化在细胞信号转导中的重要性。本文附有该论文第一作者的相关第一人称采访。
