Maldonado Horacio, Leyton Lisette
Receptor Dynamics in Cancer Laboratory, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Cellular Communication Laboratory, Programa de Biología Celular y Molecular, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Front Cell Dev Biol. 2023 Jul 7;11:1214787. doi: 10.3389/fcell.2023.1214787. eCollection 2023.
Cancer progression and metastasis are processes heavily controlled by the integrin receptor family. Integrins are cell adhesion molecules that constitute the central components of mechanosensing complexes called focal adhesions, which connect the extracellular environment with the cell interior. Focal adhesions act as key players in cancer progression by regulating biological processes, such as cell migration, invasion, proliferation, and survival. Src family kinases (SFKs) can interplay with integrins and their downstream effectors. SFKs also integrate extracellular cues sensed by integrins and growth factor receptors (GFR), transducing them to coordinate metastasis and cell survival in cancer. The non-receptor tyrosine kinase CSK is a well-known SFK member that suppresses SFK activity by phosphorylating its specific negative regulatory loop (C-terminal Y residue). Consequently, CSK may play a pivotal role in tumour progression and suppression by inhibiting SFK oncogenic effects in several cancer types. Remarkably, CSK can localise near focal adhesions when SFKs are activated and even interact with focal adhesion components, such as phosphorylated FAK and Paxillin, among others, suggesting that CSK may regulate focal adhesion dynamics and structure. Even though SFK oncogenic signalling has been extensively described before, the specific role of CSK and its crosstalk with integrins in cancer progression, for example, in mechanosensing, remain veiled. Here, we review how CSK, by regulating SFKs, can regulate integrin signalling, and focus on recent discoveries of mechanotransduction. We additionally examine the cross talk of integrins and GFR as well as the membrane availability of these receptors in cancer. We also explore new pharmaceutical approaches to these signalling pathways and analyse them as future therapeutic targets.
癌症进展和转移是受整合素受体家族严格控制的过程。整合素是细胞粘附分子，是称为粘着斑的机械传感复合物的核心组成部分，粘着斑将细胞外环境与细胞内部连接起来。粘着斑通过调节细胞迁移、侵袭、增殖和存活等生物学过程，在癌症进展中发挥关键作用。Src家族激酶（SFK）可以与整合素及其下游效应器相互作用。SFK还整合由整合素和生长因子受体（GFR）感知的细胞外信号，将它们转导以协调癌症中的转移和细胞存活。非受体酪氨酸激酶CSK是一种著名的SFK成员，它通过磷酸化其特定的负调节环（C末端Y残基）来抑制SFK活性。因此，CSK可能通过抑制几种癌症类型中的SFK致癌作用，在肿瘤进展和抑制中发挥关键作用。值得注意的是，当SFK被激活时，CSK可以定位于粘着斑附近，甚至与粘着斑成分相互作用，如磷酸化的FAK和桩蛋白等，这表明CSK可能调节粘着斑的动力学和结构。尽管之前已经广泛描述了SFK致癌信号，但CSK及其与整合素在癌症进展中的串扰，例如在机械传感中的具体作用，仍然不清楚。在这里，我们综述了CSK如何通过调节SFK来调节整合素信号，并关注机械转导的最新发现。我们还研究了整合素和GFR的串扰以及这些受体在癌症中的膜可用性。我们还探索了针对这些信号通路的新药物方法，并将它们作为未来的治疗靶点进行分析。
