Regulation of integrin growth factor interactions in oligodendrocytes by lipid raft microdomains
Regulation of integrin growth factor interactions in oligodendrocytes by lipid raft microdomains
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DOI：
10.1016/s0960-9822(02)01437-9
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发表时间：
2003-01-21
期刊：
影响因子：
9.2
通讯作者：
ffrench-Constant, C
中科院分区：
文献类型：
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作者：
Baron, W;Decker, L;ffrench-Constant, C
单个生长因子可以调节单个细胞在分化过程中的多方面行为，每个信号通路独立控制，也对其他受体(如细胞表面整合素)做出反应。实现这一目标的机制仍然知之甚少。在这里，我们使用髓鞘形成的少突胶质细胞及其前体来研究细胞膜上的脂筏、胆固醇和富含鞘磷脂的微域在细胞信号中的作用[1]。在这些细胞中，生长因子PDGF在增殖和存活中具有连续和独立的作用[2，3]。我们发现，在发育阶段，当PDGF停止促进增殖时，少突胶质细胞PDGFα受体被隔离在RAFT室中，但现在是生存所必需的。我们还表明，层粘连蛋白-2表达在中枢神经系统的轴突上，为少突胶质细胞提供靶向依赖的信号，通过扩增PDGFalphaR信号[4]来生存，诱导层粘连蛋白结合整合素α6beta1与含有PDGFalphaR的脂筏结构域聚集。这种细胞外基质诱导的整合素和生长因子受体的共定位在RAFT内为促进生存的Pl3K/Akt活性产生了一个信号环境。这些结果证明了脂筏的新的信号作用，确保了生长因子信号通路在发育过程中的分离和放大。
Individual growth factors can regulate multiple aspects of behavior within a single cell during differentiation, with each signaling pathway controlled independently and also responsive to other receptors such as cell surface integrins. The mechanisms by which this is achieved remain poorly understood. Here we use myelin-forming oligodendrocytes and their precursors to examine the role of lipid rafts, cholesterol and sphingolipid-rich microdomains of the cell membrane implicated in cell signaling [1]. In these cells, the growth factor PDGF has sequential and independent roles in proliferation and survival [2,3]. We show that the oligodendrocyte PDGFalpha receptor becomes sequestered in a raft compartment at the developmental stage when PDGF ceases to promote proliferation, but is now required for survival. We also show that laminin-2, which is expressed on axons in the CNS and which provides a target-dependent signal for oligodendrocyte, survival by amplification of PDGFalphaR signaling [4], induces clustering of the laminin binding integrin alpha6beta1 with the PDGFalphaR-containing lipid raft domains. This extra-cellular matrix-induced colocalization of integrin and growth factor receptor generates a signaling environment within the raft for survival-promoting Pl3K/Akt activity. These results demonstrate novel signaling roles for lipid rafts that ensure the separation and amplification of growth factor signaling pathways during development.