GLOBAL ANALYSIS OF SUMO E3 LIGASE SPECIFICITY UNCOVERS CROSSTALK-MEDIATED KINASE ACTIVATION

Proteomics;SUMO;Biotechnology

Uzoma, Ijeoma K.Wolberger, Cynthia ;

Johns Hopkins University

关键词: Proteomics;    SUMO;    Biotechnology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37923/UZOMA-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Over 100 kinases were recovered as SUMO substrates in our assays which points to a global phenomenon of kinase regulation by SUMO modification. The studies presented in chapter 4 describe our efforts to validate and characterize SUMO modification of focal adhesion, tyrosine kinase, Pyk2. Here, we demonstrate that SUMOylation of Pyk2 is a novel PTM that serves to amplify intrinsic kinase activity by enhancing autophosphorylation. Further biochemical studies reveal SUMOylation of Pyk2 enhances its association with putative binding protein Src kinase, promotes phosphorylation of downstream focal adhesion protein paxillin, and mediates ERK activation. These findings led us to examine the role of SUMOylation of Pyk2 in cell migration. Our results suggest SUMOylation of Pyk2 amplifies its promigratory function in MDA-MB-231 breast cancer cells. These studies have revealed a novel mechanism for Pyk2 activation, regulated by crosstalk between phosphorylation and SUMOylation. Collectively, we have illuminated the connections between SUMOylated kinases along a particular signaling axis, promoting enzyme activity, protein interactions, and activation of numerous nodes in a pathway. We believe that the work presented in this thesis will have a profound impact on the studies of SUMOylation and its crosstalk with other PTMs in a broad range of biological processes.