Telmer Patrick G, Tolg Cornelia, McCarthy James B, Turley Eva A
London Regional Cancer Program; London Health Sciences Center; Departments Oncology and Biochemistry; Schulich School of Medicine; University of Western Ontario; London, ON Canada.
Commun Integr Biol. 2011 Mar;4(2):182-5. doi: 10.4161/cib.4.2.14270.
The mechanisms responsible for the oncogenic effects of the hyaluronan (HA) receptor and mitotic spindle binding protein, RHAMM, are poorly understood. On one hand, extracellular RHAMM interacts with HA and cellsurface receptors such as CD44 to coordinately activate the MAPK/ERK1,2 pathway, thus contributing to the spread and proliferation of tumor cells. On the other hand, intracellular RHAMM decorates mitotic spindles and is necessary for spindle formation and progression through G2/M and overexpression or loss of RHAMM can result in multipole spindles and chromosome missegregation. The deregulation of these intracellular functions could lead to genomic instability and fuel tumor progression. This suggests that both extracellular and intracellular RHAMM can promote tumor progression. Intracellular RHAMM can bind directly to ERK1 to form complexes with ERK2, MEK1 and ERK1,2 substrates, and we present a model whereby RHAMM's function is as a scaffold protein, controlling activation and targeting of ERK1,2 to specific substrates.
透明质酸（HA）受体和有丝分裂纺锤体结合蛋白RHAMM的致癌作用机制目前还知之甚少。一方面，细胞外的RHAMM与HA及细胞表面受体（如CD44）相互作用，协同激活MAPK/ERK1,2信号通路，从而促进肿瘤细胞的扩散和增殖。另一方面，细胞内的RHAMM分布于有丝分裂纺锤体上，是纺锤体形成以及细胞通过G2/M期所必需的，RHAMM的过表达或缺失会导致多极纺锤体和染色体错分离。这些细胞内功能的失调可能导致基因组不稳定并推动肿瘤进展。这表明细胞外和细胞内的RHAMM都能促进肿瘤进展。细胞内的RHAMM可直接与ERK1结合，与ERK2、MEK1以及ERK1,2的底物形成复合物，我们提出了一个模型，即RHAMM作为一种支架蛋白，控制ERK1,2对特定底物的激活和靶向作用。
