Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Jixin Dong

Abstract

The Hippo signaling pathway, originally discovered in Drosophila, consists of a core kinase cascade and has been subsequently demonstrated to control tissue growth and tumorigenesis. The core of this pathway contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP) and PDZ-binding motif (TAZ). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP/TAZ from translocating to nucleus, thereby suppressing the expression of downstream pro-growth and survival genes. While recent studies provide important insight into the tumor suppressor properties of this pathway, the underlying molecular mechanisms through which the Hippo components exert their oncogenic/suppressing function are poorly understood. Zyxin and LIM domains containing 1 (LIMD1) are adaptor/scaffold proteins with three LIM domains, which are involved in protein-protein interactions during cellular signaling transduction. Several recent studies showed that Zyxin/LIMD1 affect Hippo-YAP signaling. Our studies found that Zyxin and LIMD1 are phosphorylated in mitosis via novel sites. We further characterized the phospho-regulation of Zyxin and LIMD1 in mitosis and examined the functional significance of the phosphorylation in colon cancer and lung cancer, respectively. Moreover, we demonstrated that Zyxin regulates YAP activity through colon cancer oncogene Cyclin-Dependent Kinase 8 (CDK8). Mechanistically, we identified that CDK8 directly phosphorylates YAP and promotes its activation. Together, our findings revealed novel layers of regulation for Zyxin/LIMD1 in mitosis and their roles in tumorigenesis.

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