Chong Yuh-Ping, Mulhern Terrence D, Cheng Heung-Chin
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Department of Biochemistry and Molecular Biology, Parkville, Victoria, Australia.
Growth Factors. 2005 Sep;23(3):233-44. doi: 10.1080/08977190500178877.
C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors of the Src-family protein tyrosine kinases (SFKs). Since constitutive activation of SFKs contributes to cancer formation and progression, to prevent excessive activation of SFKs, their activity in normal cells is kept at the basal level by CSK and CHK. CSK and CHK inactivate SFKs by specifically phosphorylating a consensus tyrosine (called Y(T)) near their C-termini. Upon phosphorylation, the phospho-Y(T) engages in intramolecular interactions that lock the SFK molecule in an inactive conformation. SFKs are anchored to the plasma membrane, while CSK and CHK are localized predominantly in the cytosol. To inhibit SFKs, CSK and CHK need to translocate to the plasma membrane. Recruitment of CSK and CHK to the plasma membrane is mediated by the binding of their SH2, SH3 and/or kinase domains to specific transmembrane proteins, G-proteins and adaptor proteins located near the plasma membrane. For CSK, membrane recruitment often accompanies activation. CSK and CHK employ two types of direct interactions with SFKs to achieve efficient Y(T) phosphorylation: (i) short-range interactions involving binding of the active sites of CSK and CHK to specific residues near Y(T), (ii) long-range non-catalytic interactions involving binding of SFKs to motifs located distally from the active sites of CSK and CHK. The interactions between CSK and SFKs are transient in nature. Unlike CSK, CHK binds tightly to SFKs to form stable protein complexes. The binding is non-catalytic as it is independent of Y(T). More importantly, the tight binding alone is sufficient to completely inhibit SFKs. This non-catalytic inhibitory binding represents a novel mechanism employed by CHK to inhibit SFKs. Given that SFKs are implicated in cancer development, compounds mimicking the non-catalytic inhibitory mechanism of CHK are potential anti-cancer therapeutics.
C 端 Src 激酶（CSK）和 CSK 同源激酶（CHK）是 Src 家族蛋白酪氨酸激酶（SFK）的内源性抑制剂。由于 SFK 的组成性激活促进癌症的形成和进展，为防止 SFK 的过度激活，CSK 和 CHK 将其在正常细胞中的活性维持在基础水平。CSK 和 CHK 通过特异性磷酸化 SFK 靠近其 C 端的一个共有酪氨酸（称为 Y(T)）来使其失活。磷酸化后，磷酸化的 Y(T) 参与分子内相互作用，将 SFK 分子锁定在无活性构象中。SFK 锚定在质膜上，而 CSK 和 CHK 主要定位于细胞质中。为了抑制 SFK，CSK 和 CHK 需要转位到质膜。CSK 和 CHK 被招募到质膜是由它们的 SH2、SH3 和/或激酶结构域与位于质膜附近的特定跨膜蛋白、G 蛋白和衔接蛋白的结合介导的。对于 CSK，膜募集通常伴随着激活。CSK 和 CHK 与 SFK 采用两种直接相互作用来实现有效的 Y(T) 磷酸化：（i）涉及 CSK 和 CHK 的活性位点与 Y(T) 附近特定残基结合的短程相互作用，（ii）涉及 SFK 与位于 CSK 和 CHK 活性位点远端的基序结合的长程非催化相互作用。CSK 和 SFK 之间的相互作用本质上是短暂的。与 CSK 不同，CHK 与 SFK 紧密结合形成稳定的蛋白质复合物。这种结合是非催化性的，因为它不依赖于 Y(T)。更重要的是，仅这种紧密结合就足以完全抑制 SFK。这种非催化性抑制结合代表了 CHK 抑制 SFK 所采用的一种新机制。鉴于 SFK 与癌症发展有关，模拟 CHK 非催化性抑制机制的化合物是潜在的抗癌治疗药物。
