Rap1 Negatively Regulates the Hippo Pathway to Polarize Directional Protrusions in Collective Cell Migration
Yu-Chiuan Chang,
Jhen-Wei Wu,
Yi-Chi Hsieh,
Tzu-Han Huang,
Zih-Min Liao,
Yi-Shan Huang,
James A. Mondo,
Denise Montell,
Anna C.-C. Jang
Affiliations
Yu-Chiuan Chang
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
Jhen-Wei Wu
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China
Yi-Chi Hsieh
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China
Tzu-Han Huang
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China
Zih-Min Liao
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China
Yi-Shan Huang
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China
James A. Mondo
Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA
Denise Montell
Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA
Anna C.-C. Jang
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China; Corresponding author
Summary: In collective cell migration, directional protrusions orient cells in response to external cues, which requires coordinated polarity among the migrating cohort. However, the molecular mechanism has not been well defined. Drosophila border cells (BCs) migrate collectively and invade via the confined space between nurse cells, offering an in vivo model to examine how group polarity is organized. Here, we show that the front/back polarity of BCs requires Rap1, hyperactivation of which disrupts cluster polarity and induces misoriented protrusions and loss of asymmetry in the actin network. Conversely, hypoactive Rap1 causes fewer protrusions and cluster spinning during migration. A forward genetic screen revealed that downregulation of the Hippo (Hpo) pathway core components hpo or mats enhances the Rap1V12-induced migration defect and misdirected protrusions. Mechanistically, association of Rap1V12 with the kinase domain of Hpo suppresses its activity, which releases Hpo signaling-mediated suppression of F-actin elongation, promoting cellular protrusions in collective cell migration.
