Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.
Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.
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DOI：
10.1083/jcb.200404076
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发表时间：
2004-10-25
影响因子：
7.8
通讯作者：
ffrench-Constant, Charles
中科院分区：
文献类型：
--
作者：
Colognato, Holly;Ramachandrappa, Shwetha;Olsen, Inger M;ffrench-Constant, Charles
在中枢神经系统的髓鞘形成细胞少突胶质细胞上表达的特异性整合素，通过放大生长因子信号传导促进分化、存活或增殖。在这里，我们报告了Src家族激酶（SFKs） Fyn和Lyn调节这些不同的整合素驱动行为。Fyn与α6β1相关，可以放大血小板来源的生长因子生存信号，促进髓鞘膜的形成，并将神经调节蛋白信号从磷脂酰肌醇3-激酶转变为丝裂原激活的蛋白激酶途径（从而将反应从增殖转变为分化）。然而，在谱系的早期，Lyn而不是Fyn是驱动α v β3依赖性祖细胞增殖所必需的。两种sfk通过不同的机制响应整合素连接：Lyn，通过增加催化酪氨酸的自磷酸化；和Fyn，通过减少抑制cooh末端酪氨酸的Csk磷酸化。这些发现说明了不同的SFKs如何在单个细胞谱系的发育过程中作为特定细胞反应的效应物，并且进一步提供了一种分子机制来解释层粘连蛋白和fyn缺陷小鼠中类似的区域特异性髓鞘形成低下。
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with α6β1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive αVβ3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.