Platelet-derived growth factor - Distinct signal transduction pathways associated with migration versus proliferation
Platelet-derived growth factor - Distinct signal transduction pathways associated with migration versus proliferation
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DOI：
10.1111/j.1749-6632.1995.tb26691.x
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发表时间：
1995-01-01
期刊：
影响因子：
--
通讯作者：
Ross, R
中科院分区：
文献类型：
--
作者：
Bornfeldt, KE;Raines, EW;Ross, R
图2总结了我们目前对激活的PDGF受体参与人类动脉SMC定向迁移和增殖的信号数据的解释。PDGF的结合（PDGF- bb或PDGF- aa）导致PDGF受体二聚化，酪氨酸自磷酸化，随后将含有SH2结构域的几个分子结合到活化的受体上。PDGF受体结合和激活PLC γ导致PIP2水解，产生二酰基甘油（DAG）和IP3。随后，由于ip3介导的钙从细胞内区室释放，细胞内钙水平升高。PIP2水平的降低和钙水平的升高都有利于肌动蛋白丝的分解，通过诱导肌动蛋白丝倒钩末端的封顶和肌动蛋白单体的隔离。局部的、瞬时的肌动蛋白丝分解使细胞向PDGF方向延伸丝状足，从而使趋化发生。在稍后的时间和/或在不同的隔室中，PDGF通过一种尚不完全清楚的机制促进肌动蛋白-丝的组装，但可能涉及小的gtp结合蛋白，如Rho，和DAG的形成。在胶原蛋白上的迁移需要功能性的α 2 β 1整合素，它可能构成细胞迁移所需的允许状态，也可能积极参与导致迁移的细胞内信号。pdgf诱导的DNA合成和增殖涉及Ras、MAP激酶和MAP激酶的激活。PKA信号和酪氨酸激酶受体信号之间的串扰导致PKA抑制MAP激酶级联反应，可能在Raf水平上。PI 3-激酶或PI 3-激酶样酶的激活也可能有助于PDGF在这些细胞中的有丝分裂作用（Bornfeldt，未发表的观察结果）。是什么决定SMC是否会迁移和/或增殖以响应PDGF？研究结果开始显示SMC不同表型状态下参与细胞内信号传导的分子的表达调控。例如，PLC γ的表达在完整的血管壁中非常低（其中SMC显示“收缩表型”），并且在SMC在培养中转化为“合成表型”时被诱导。MAP激酶的增殖和表达，而不是钙信号，似乎受细胞外基质的调节，并且在培养的SMC中整合素的表达谱与血管壁中的SMC不同。因此，参与迁移的信号分子与参与增殖的信号分子的表达之间的关系，以及不同信号转导途径之间的串扰，可能决定了PDGF的净效应。
Figure 2 summarizes our current interpretation of data concerning signals from the activated PDGF receptor involved in directed migration and proliferation of human arterial SMC. Binding of PDGF (PDGF-BB or PDGF-AA) causes PDGF-receptor dimerization, tyrosine autophosphorylation, and subsequent binding of several molecules containing SH2 domains to the activated receptor. Binding and activation of PLC gamma by the PDGF receptor leads to PIP2 hydrolysis, resulting in generation of diacylglycerol (DAG) and IP3. Subsequently, intracellular levels of calcium are elevated as a result of IP3-mediated calcium release from intracellular compartments. The decreased levels of PIP2 and increased levels of calcium both favor actin-filament disassembly by inducing capping of actin-filament barbed ends and actin-monomer sequestration. A localized, and transient, actin-filament disassembly enables the cell to extend filopodia towards PDGF, thereby enabling chemotaxis to take place. At a later time and/or in a different compartment, actin-filament assembly is promoted by PDGF by a mechanism that is not completely understood, but that may involve small GTP-binding proteins, such as Rho, and formation of DAG. Migration on collagen requires functional alpha 2 beta 1 integrins, which may either constitute a permissive state required for a cell to migrate, or which may be actively involved in intracellular signals leading to migration. PDGF-induced DNA synthesis and proliferation involves activation of Ras, MAP kinase kinase, and MAP kinase. Cross-talk between PKA signaling and tyrosine-kinase receptor signaling results in PKA inhibition of the MAP kinase cascade, probably at the level of Raf. Activation of PI 3-kinase, or a PI 3-kinase-like enzyme, is also likely to contribute to the mitogenic effects of PDGF in these cells (Bornfeldt, unpublished observation). What determines if a SMC will migrate and/or proliferate in response to PDGF? Results are starting to emerge that show regulation of expression of molecules involved in intracellular signaling with different phenotypic states of SMC. For example, expression of PLC gamma is very low in intact vascular wall (where SMC show a" contractile phenotype"), and induced when SMC are converted to a" synthetic phenotype" in culture. Proliferation and expression of MAP kinase, but not calcium signaling, appear to be regulated by the extracellular matrix, and the profile of integrin expression is different in SMC in culture compared to SMC in the vascular wall. Thus, the relation between expression of signaling molecules involved in migration and signaling molecules involved in proliferation, as well as cross-talk between different signal-transduction pathways, may determine the net effect of PDGF.