Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biochemistry

First Advisor's Name

Alejandro Barbieri

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Javier Francisco-Ortega

Second Advisor's Committee Title

committee member

Third Advisor's Name

John Makemson

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

Xiaotang Wang

Fourth Advisor's Committee Title

committee member

Keywords

EGFR signaling, RIN1, Cortactin, cancer cell migration

Date of Defense

11-8-2019

Abstract

Growth factors play an essential role in abnormalities in both intracellular trafficking and signal transduction pathways responsible in normal and cancer cells. Growth factors, such as epidermal growth factor, represent a main course on the activation of mitogenic signal that contribute to the mitogen activated protein kinase (MAPK) pathway affecting cell proliferation, which is driven by Ras GTPases. However, it also induces a profound morphological change by reorganization actin and other cytoskeleton proteins, which are driven by other GTPases (i.e., Rho and Rac). Ras interference 1 (Rin1) is a key cytosolic protein, that regulates both membrane trafficking and signaling pathways through the Rin1:Vps9, which activates Rab5, and Rin1:RA, which interacts with Ras, respectively. In addition, Rin1 proline rich domain (Rin1: PR) may also help to orchestrate this complex regulation by interacting with Cortactin, which is a key molecule in actin organization at the plasma membrane via Cortactin:SH3 domain. Thus, it is possible connection between Rin1, an effector of the active form of Ras as well as an activator of Rab5, and subsequent interaction with Cortactin is of particular interest as Cortactin is frequently overexpressed in cancers. In this study, Rin1 works with a dual action: First, it sequesters Cortactin and thus, it blocks the cellular migration and invasion driven by Cortactin. Second, interaction of RIN1 with Ras in the GTP-bound form decreased serine phosphorylation of Cortactin. This inhibitory effect of RIN1 on the phosphorylation of Cortactin may be due since the interaction of Ras, which blocks both Erk and Akt activities upon EGF stimulation. In addition, Rin1 inhibits cell proliferation in cancer cells through Ras-Raf-Erk and PI3K-AKT signaling cascades by selectively affecting FOXO1 and c-Myc. This selective inhibitory effect seems to be observed on breast cancer cells but not in other cancer cell lines (human melanoma and human glioblastoma cells). In summary, this current research discovered a new activity for RIN1 in metastatic breast cancer cell lines. It interacts with Cortactin, and also decreases Cortactin function, which as an enhancer of tumorigenic activity. Thus, Rin1 may play a novel tumor suppressor role in modulating signaling through the Ras/MAPK and Ras/Akt pathways upon EGF stimulation.

Identifier

FIDC008833

Available for download on Sunday, October 17, 2021

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