脊椎动物酪氨酸激酶基因家族差异进化研究

The Study on the Differential Evolution of Protein Tyrosine Kinase Gene Family in Vertebrates

酪氨酸激酶（PTKs）基因家族是后生动物信号网络的核心组分,在细胞通讯、细胞粘附、细胞增殖和分化过程中起着关键作用,与人类许多疾病的发展密切相关。根据结构的不同,PTKs可分为两类：胞质型酪氨酸激酶（CTKs）和受体型酪氨酸激酶（RTKs）。通过多角度进化分析,我们发现在脊椎动物进化过程中RTKs比CTKs经历了纯化选择压力的放松,拥有更复杂的谱系,发生了更显著的规模扩张和成员基因间的功能分化,组织表达分化更明显,催化更特异的底物发生磷酸化,参与更特异的细胞生化过程和作用通路,这些共同说明RTKs比CTKs功能上更加特化。我们推测RTKs和CTKs倍增后的差异进化和它们不同的亚细胞定位有关：CTKs位于胞质中,受到细胞内严格稳态环境更强烈的纯化选择,进化保守;而RTKs结合在膜上,细胞外基质中生长因子变化的浓度梯度、多样化的分泌型配体分子等因素可能提供选择优势,驱动RTKs发生微弱的加速进化和更显著的功能分化以适应脊椎动物体细胞胞外环境中的小幅变化。

Protein tyrosine kinases（PTKs） are the core components of metazoan signaling networks,playing key roles in intercellular communication,cell adhesion,cell proliferation and differentiation.In human,proteintyrosine kinases have been proven to associate with many diseases.According to their different structure,PTKs can be classified into two groups：cytoplasmic tyrosine kinases（CTKs） and receptor tyrosine kinases（RTKs）.Through diverse evolutionary analyses,we found that RTKs experience more relaxed purifying selection than CTKs in the vertebrate evolution.RTKs have more complex repertoire,more prominent expansion in scale and functional divergence among member genes.They also have more clear tissue expression diversification,catalyze more specific phosphorylation for substrates,and participate in more specific cellular biochemical processes and pathways.These evidences propose that RTKs are more functionally specialized than CTKs.We infer that the differential evolution between RTKs and CTKs after duplication is due to their different subcellular localization：CTKs are in cytoplasm and under the stronger purifying selection in the stringent intracellular homeostasis and thus evolutionarily conserved;while RTKs are membrane-binding,the changing diffusion gradients of various growth factors and the diversification of secretory ligand molecules in extracellular matrix likely provided selection advantages,driving RTKs to experience weak accelerated evolution which further functionally diverged RTKs in order to adapt to the moderate changes in vertebrate extracellular environments.