Covalently Immobilizing Interferon-γ Drives Filopodia Production through Specific Receptor-Ligand Interactions Independently of Canonical Downstream Signaling.
Covalently Immobilizing Interferon-γ Drives Filopodia Production through Specific Receptor-Ligand Interactions Independently of Canonical Downstream Signaling.
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DOI：
10.1021/acs.bioconjchem.0c00105
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发表时间：
2020-05-20
影响因子：
4.7
通讯作者：
Smith, Adam W.
中科院分区：
文献类型：
--
作者：
Christie, Shaun M.;Ham, Trevor R.;Gilmore, Grant T.;Toth, Paul D.;Leipzig, Nic D.;Smith, Adam W.
固定化信号蛋白以指导细胞行为已被广泛应用于各种研究中。这种方法从生物学中获得灵感，其中膜受体和细胞外基质中固定蛋白之间的特异性亲和相互作用指导了许多发育和稳态过程。然而，合成固定化方法不一定概括体内信号系统，并可能导致人工受体-配体相互作用。为了研究工程受体-配体相互作用的一个例子的影响，我们将重点放在干扰素-γ (IFN-γ)的固定化上，干扰素-γ已被用于驱动神经干细胞（NSCs）的分化。为了分离配体固定化的影响，我们只用干扰素γ受体1 （IFNγ r1）转染Cos-7细胞，而不转染IFNγ r2，使细胞能够结合IFN-γ，但不能进行典型的信号转导。然后，我们将细胞暴露于含有共价固定IFN-γ的表面，并研究了膜形态、受体-配体动力学和受体激活。我们发现，将细胞暴露于固定但不溶的IFN-γ中，可以驱动NSCs和Cos-7中丝状足的形成，这表明共价固定IFN-γ足以影响细胞行为，而不依赖于典型的下游信号传导。总的来说，这项工作表明，合成生长因子固定可以通过延长信号持续时间或由蛋白质固定激活的空间模式来影响细胞形态，而不仅仅是增强典型细胞反应。这表明，当IFN-γ共价固定时，NSCs的分化可能由典型和非典型途径驱动。这一发现对指导细胞行为的生物工程方法具有广泛的意义，因为即使细胞缺乏典型的信号转导机制，一个配体也有可能影响多种途径。
Immobilizing a signaling protein to guide cell behavior has been employed in a wide variety of studies. This approach draws inspiration from biology, where specific, affinity-based interactions between membrane receptors and immobilized proteins in the extracellular matrix guide many developmental and homeostatic processes. Synthetic immobilization approaches, however, do not necessarily recapitulate the in vivo signaling system and potentially lead to artificial receptor-ligand interactions. To investigate the effects of one example of engineered receptor-ligand interactions, we focus on the immobilization of interferon-γ (IFN-γ), which has been used to drive differentiation of neuronal stem cells (NSCs). To isolate the effect of ligand immobilization, we transfected Cos-7 cells with only interferon-γ receptor 1 (IFNγR1), not IFNγR2, so that the cells could bind IFN-γ, but were incapable of canonical signal transduction. We then exposed the cells to surfaces containing covalently immobilized IFN-γ and studied membrane morphology, receptor-ligand dynamics, and receptor activation. We found that exposing cells to immobilized, but not soluble IFN-γ, drove the formation of filopodia in both NSCs and Cos-7, showing that covalently immobilizing IFN-γ is enough to affect cell behavior, independently of canonical downstream signaling. Overall, this work suggests that synthetic growth factor immobilization can influence cell morphology beyond enhancing canonical cell responses through the prolonged signaling duration or spatial patterning enabled by protein immobilization. This suggests that differentiation of NSCs could be driven by canonical and non-canonical pathways when IFN-γ is covalently immobilized. This finding has broad implications for bioengineering approaches to guide cell behavior, as one ligand has the potential to impact multiple pathways even when cells lack the canonical signal transduction machinery.
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DOI：
10.1083/jcb.200503140
发表时间：
2005-08-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lidke DS;Lidke KA;Rieger B;Jovin TM;Arndt-Jovin DJ
通讯作者：
Arndt-Jovin DJ
影响因子：
6
作者：
Farrag, Mahmoud;Leipzig, Nic D.
通讯作者：
Leipzig, Nic D.
影响因子：
2.9
作者：
Jastrzebska, Beata;Comar, William D.;Smith, Adam W.
通讯作者：
Smith, Adam W.
影响因子：
3.7
作者：
Li H;Xie YH;Yang Q;Wang SW;Zhang BL;Wang JB;Cao W;Bi LL;Sun JY;Miao S;Hu J;Zhou XX;Qiu PC
通讯作者：
Qiu PC
影响因子：
3.4
作者：
Marita, Morgan;Wang, Yuxiao;Smith, Adam W.
通讯作者：
Smith, Adam W.