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Cellular Oncology
Published in: Cellular Oncology 6/2021

Open Access 01-12-2021 | Colorectal Cancer | Original Article

Beta-Pix-dynamin 2 complex promotes colorectal cancer progression by facilitating membrane dynamics

Authors: Seula Keum, Soo Jung Yang, Esther Park, TaeIn Kang, Jee-Hye Choi, Jangho Jeong, Ye Eun Hwang, Jung-Woong Kim, Dongeun Park, Sangmyung Rhee

Published in: Cellular Oncology | Issue 6/2021

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Abstract

Purpose

Spatiotemporal regulation of cell membrane dynamics is a major process that promotes cancer cell invasion by acting as a driving force for cell migration. Beta-Pix (βPix), a guanine nucleotide exchange factor for Rac1, has been reported to be involved in actin-mediated cellular processes, such as cell migration, by interacting with various proteins. As yet, however, the molecular mechanisms underlying βPix-mediated cancer cell invasion remain unclear.

Methods

The clinical significance of βPix was analyzed in patients with colorectal cancer (CRC) using public clinical databases. Pull-down and immunoprecipitation assays were employed to identify novel binding partners for βPix. Additionally, various cell biological assays including immunocytochemistry and time-lapse video microscopy were performed to assess the effects of βPix on CRC progression. A βPix-SH3 antibody delivery system was used to determine the effects of the βPix-Dyn2 complex in CRC cells.

Results

We found that the Src homology 3 (SH3) domain of βPix interacts with the proline-rich domain of Dynamin 2 (Dyn2), a large GTPase. The βPix-Dyn2 interaction promoted lamellipodia formation, along with plasma membrane localization of membrane-type 1 matrix metalloproteinase (MT1-MMP). Furthermore, we found that Src kinase-mediated phosphorylation of the tyrosine residue at position 442 of βPix enhanced βPix-Dyn2 complex formation. Disruption of the βPix-Dyn2 complex by βPix-SH3 antibodies targeting intracellular βPix inhibited CRC cell invasion.

Conclusions

Our data indicate that spatiotemporal regulation of the Src-βPix-Dyn2 axis is crucial for CRC cell invasion by promoting membrane dynamics and MT1-MMP recruitment into the leading edge. The development of inhibitors that disrupt the βPix-Dyn2 complex may be a useful therapeutic strategy for CRC.
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Metadata
Title
Beta-Pix-dynamin 2 complex promotes colorectal cancer progression by facilitating membrane dynamics
Authors
Seula Keum
Soo Jung Yang
Esther Park
TaeIn Kang
Jee-Hye Choi
Jangho Jeong
Ye Eun Hwang
Jung-Woong Kim
Dongeun Park
Sangmyung Rhee
Publication date
01-12-2021
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 6/2021
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-021-00637-6

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