Worrall Claire, Nedelcu Daniela, Serly Julianna, Suleymanova Naida, Oprea Iulian, Girnita Ada, Girnita Leonard
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden.
Pediatr Endocrinol Rev. 2013 Jul;10(4):473-84.
The IGF-1R pathway is essential for the initiation and progression of many cancers. In contrast to other receptor tyrosine kinases involved in cancer, it is not frequently mutated or amplified. The classical model of signaling through the IGF-1R centers on ligand initiated kinase activation, allowing binding of adaptor molecules and downstream activation of the MAPK and PI3K pathways. The signaling is terminated through receptor ubiquitination and subsequent degradation. To date, therapies targeting IGF-1R have been designed solely aiming to block phosphorylation mediated signaling by preventing receptor-ligand interaction or by limiting kinase activation. Yet, the classical model is insufficient to explain receptor behavior induced by some IGF-1R inhibitors. This review advocates an updated model of IGF-1R signaling, accommodating the "classical" kinase signaling and the IGF-1R-kinase independent signaling thus providing the theoretical background for receptor downregulation induced by IGF-1R inhibitors. This model should be considered for future design of effective therapies targeting the IGF-1R pathway.
IGF-1R信号通路对许多癌症的起始和进展至关重要。与参与癌症的其他受体酪氨酸激酶不同，它不常发生突变或扩增。通过IGF-1R进行信号传导的经典模型以配体启动的激酶激活为核心，允许衔接分子结合并下游激活MAPK和PI3K通路。信号通过受体泛素化和随后的降解而终止。迄今为止，靶向IGF-1R的疗法仅旨在通过阻止受体-配体相互作用或限制激酶激活来阻断磷酸化介导的信号传导。然而，经典模型不足以解释某些IGF-1R抑制剂诱导的受体行为。本综述提倡一种更新的IGF-1R信号传导模型，兼顾“经典”激酶信号传导和IGF-1R激酶非依赖性信号传导，从而为IGF-1R抑制剂诱导的受体下调提供理论背景。在未来设计靶向IGF-1R通路的有效疗法时应考虑该模型。
