Date of Award
12-9-2016
Document Type
Dissertation
Degree Name
Molecular Biosciences, Ph.D.
First Advisor
Guolei Zhou
Committee Members
Anne Grippo; Fabricio Medina-Bolivar; Jeffery Field; Jianfeng Xu
Call Number
LD251 .A566d 2016 Z43
Abstract
CAP is a conserved actin-binding protein with versatile roles in promoting actin dynamics across species. Mammalian CAPs had been understudied compared to the first identified yeast homologues; their cellular functions remained to be better established. Moreover, CAP function regulation remained a completely uncharted area. Recent studies also implicated CAP in the invasiveness of human cancers. However, some of the evidence was not convincing and further studies were needed. The present study established and identified new cellular functions for mammalian CAP1, identified a regulatory mechanism as phosphorylation at the S307/S309 tandem site along with the cell signals controlling both phosphorylation and de-phosphorylation, and unraveled cell context-dependent functions for CAP1 in the invasiveness and proliferation of breast cancer cells. Specifically, the study firstly established the roles for CAP1 in regulating actin-directed subcellular structures important for cell migration. CAP1 knockdown caused the accumulation of stress fibers and stimulated the formation of lamellipodia and focal adhesions, with the activated FAK (focal adhesion kinase) and cell adhesion signaling underlying the latter phenotype. CAP1 also regulated the activity of ADF /cofilin. Secondly, the study demonstrated that phosphorylation at S307/S309 controlled the subcellular localization and the activity of CAP1 in interacting with cofilin and actin, that the transient phosphorylation was critically important for CAP1 to regulate actin filament turnover and the formation of focal adhesions and lamellipodia. CDK5 phosphorylated both the residues, while GSK3 phosphorylated S309 only. Antagonistically, activated cAMP signaling led to the de-phosphorylation of CAP1. Finally, the study identified cell context-dependent roles for CAP1 in the invasiveness as well as proliferation of breast cancer cells. In the metastatic breast cancer cells, depletion of CAP1 led to elevated invasiveness, cell proliferation and anchorage-independent growth. In the non-metastatic cells, the knockdown actually caused the opposite effects. Importantly, the FAK-ERK signaling was identified to be responsible for mediating both the effects on the invasiveness and proliferation of cancer cells. Together, the present study links cell signaling to the actin cytoskeleton, as well as cancerous transformation and cancer invasiveness; the mechanistic insights may ultimately lead to strategies targeting CAP1 and its upstream regulatory signals for cancer treatment.
Rights Management
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Zhang, Haitao, "The Study of the Functions and Regulation of Mammalian CAP1 (Cyclase-Associated Protein 1)" (2016). Student Theses and Dissertations. 591.
https://arch.astate.edu/all-etd/591
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Biology Commons, Cancer Biology Commons, Molecular Biology Commons
