Holt Lowenna J, Siddle Kenneth
University of Cambridge, Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, UK.
Biochem J. 2005 Jun 1;388(Pt 2):393-406. doi: 10.1042/BJ20050216.
The Grb proteins (growth factor receptor-bound proteins) Grb7, Grb10 and Grb14 constitute a family of structurally related multidomain adapters with diverse cellular functions. Grb10 and Grb14, in particular, have been implicated in the regulation of insulin receptor signalling, whereas Grb7 appears predominantly to be involved in focal adhesion kinase-mediated cell migration. However, at least in vitro, these adapters can bind to a variety of growth factor receptors. The highest identity within the Grb7/10/14 family occurs in the C-terminal SH2 (Src homology 2) domain, which mediates binding to activated receptors. A second well-conserved binding domain, BPS [between the PH (pleckstrin homology) and SH2 domains], can act to enhance binding to the IR (insulin receptor). Consistent with a putative adapter function, some non-receptor-binding partners, including protein kinases, have also been identified. Grb10 and Grb14 are widely, but not uniformly, expressed in mammalian tissues, and there are various isoforms of Grb10. Binding of Grb10 or Grb14 to autophosphorylated IR in vitro inhibits tyrosine kinase activity towards other substrates, but studies on cultured cell lines have been conflicting as to whether Grb10 plays a positive or negative role in insulin signalling. Recent gene knockouts in mice have established that Grb10 and Grb14 act as inhibitors of intracellular signalling pathways regulating growth and metabolism, although the phenotypes of the two knockouts are distinct. Ablation of Grb14 enhances insulin action in liver and skeletal muscle and improves whole-body tolerance, with little effect on embryonic growth. Ablation of Grb10 results in disproportionate overgrowth of the embryo and placenta involving unidentified pathways, and also impacts on hepatic glycogen synthesis, and probably on glucose homoeostasis. This review discusses the extent to which previous studies in vitro can account for the observed phenotype of knockout animals, and considers evidence that aberrant function of Grb10 or Grb14 may contribute to disorders of growth and metabolism in humans.
Grb蛋白（生长因子受体结合蛋白）Grb7、Grb10和Grb14构成了一个结构相关的多结构域衔接蛋白家族，具有多种细胞功能。特别是Grb10和Grb14，已被证实参与胰岛素受体信号传导的调节，而Grb7似乎主要参与粘着斑激酶介导的细胞迁移。然而，至少在体外，这些衔接蛋白能与多种生长因子受体结合。Grb7/10/14家族中最高的同源性出现在C端的SH2（Src同源2）结构域，该结构域介导与活化受体的结合。第二个保守性良好的结合结构域BPS（位于PH结构域和SH2结构域之间）可增强与胰岛素受体（IR）的结合。与假定的衔接蛋白功能一致，还鉴定出了一些非受体结合伙伴，包括蛋白激酶。Grb10和Grb14在哺乳动物组织中广泛但并非均匀表达，并且Grb10有多种异构体。在体外，Grb10或Grb14与自身磷酸化的IR结合会抑制酪氨酸激酶对其他底物的活性，但关于Grb10在胰岛素信号传导中起正向还是负向作用，培养细胞系的研究结果一直存在矛盾。最近对小鼠的基因敲除研究表明，Grb10和Grb14作为调节生长和代谢的细胞内信号通路的抑制剂，尽管两种基因敲除的表型不同。敲除Grb14可增强肝脏和骨骼肌中的胰岛素作用，并改善全身耐受性，对胚胎生长影响较小。敲除Grb10会导致胚胎和胎盘过度生长，涉及不明途径，还会影响肝糖原合成，可能还会影响葡萄糖稳态。本综述讨论了以往体外研究在多大程度上能够解释基因敲除动物所观察到的表型，并考虑了Grb10或Grb14功能异常可能导致人类生长和代谢紊乱的证据。
